U.S. patent number 9,498,470 [Application Number 14/379,028] was granted by the patent office on 2016-11-22 for antiviral drugs for treatment of arenavirus infection.
This patent grant is currently assigned to Kineta Four, LLC. The grantee listed for this patent is KINETA FOUR, LLC. Invention is credited to Sean M. Amberg, James R. Burgeson, Dongcheng Dai, Dennis E. Hruby.
United States Patent |
9,498,470 |
Dai , et al. |
November 22, 2016 |
Antiviral drugs for treatment of arenavirus infection
Abstract
Compounds, methods and pharmaceutical compositions for treating
viral infections, by administering certain compounds in
therapeutically effective amounts are disclosed. Methods for
preparing the compounds and methods of using the compounds and
pharmaceutical compositions thereof are also disclosed. In
particular, the treatment and prophylaxis of viral infections such
as caused by the Arenavirus family such as Lassa fever, Argentine
hemorrhagic fever, Bolivian hemorrhagic fever, and Venezuelan
hemorrhagic fever.
Inventors: |
Dai; Dongcheng (Corvallis,
OR), Burgeson; James R. (Albany, OR), Amberg; Sean M.
(Corvallis, OR), Hruby; Dennis E. (Albany, OR) |
Applicant: |
Name |
City |
State |
Country |
Type |
KINETA FOUR, LLC |
Seattle |
WA |
US |
|
|
Assignee: |
Kineta Four, LLC (Seattle,
WA)
|
Family
ID: |
48984889 |
Appl.
No.: |
14/379,028 |
Filed: |
February 14, 2013 |
PCT
Filed: |
February 14, 2013 |
PCT No.: |
PCT/US2013/026173 |
371(c)(1),(2),(4) Date: |
August 15, 2014 |
PCT
Pub. No.: |
WO2013/123215 |
PCT
Pub. Date: |
August 22, 2013 |
Prior Publication Data
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Document
Identifier |
Publication Date |
|
US 20150023916 A1 |
Jan 22, 2015 |
|
Related U.S. Patent Documents
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Application
Number |
Filing Date |
Patent Number |
Issue Date |
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61600036 |
Feb 17, 2012 |
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Current U.S.
Class: |
1/1 |
Current CPC
Class: |
A61K
31/437 (20130101); C07D 235/08 (20130101); A61P
31/14 (20180101); C07D 235/06 (20130101); A61P
43/00 (20180101); C07D 401/04 (20130101); A61K
31/4439 (20130101); A61P 31/12 (20180101); C07D
401/10 (20130101); C07D 405/10 (20130101); C07D
209/08 (20130101); A61K 31/404 (20130101); A61K
45/06 (20130101); C07D 471/04 (20130101); A61K
31/4184 (20130101) |
Current International
Class: |
C07D
235/06 (20060101); C07D 471/04 (20060101); C07D
401/04 (20060101); A61K 31/4439 (20060101); A61K
31/404 (20060101); C07D 209/08 (20060101); A61K
31/4184 (20060101); A61K 31/437 (20060101); A61K
45/06 (20060101) |
Field of
Search: |
;548/304.4 |
References Cited
[Referenced By]
U.S. Patent Documents
Foreign Patent Documents
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63-157157 |
|
Jun 1988 |
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JP |
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04-46352 |
|
Feb 1992 |
|
JP |
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WO-95/04723 |
|
Feb 1995 |
|
WO |
|
Other References
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Registry file on STN CAS Online Apr. 4, 2007. cited by examiner
.
Mader et al., Bioorganic & Medicinal Chemistry Letters (2008),
18(1), pp. 179-183. cited by examiner .
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168630-06-6. cited by examiner .
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by examiner .
An English translation of Shiino et al., JP 63-157157 A, 1988.
cited by examiner .
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by examiner .
International Search Report and Written Opinion issued in parent
International Application No. PCT/US13/26173, dated Apr. 26, 2014.
cited by applicant .
Extended European Search Report mailed Jun. 6, 2016, issued in
corresponding European Application No. 13749809.3, filed Feb. 14,
2013, 10 pages. cited by applicant .
Patent Examination Report No. 2, mailed Jun. 23, 2016, issued in
Australian Patent Application No. 2013221475, filed Feb. 14, 2013,
4 pages. cited by applicant .
Solanki, S., et al., Benzimidazole Inhibitors Induce a DFG-Out
Conformation of Never in Mitosis Gene A-Related Kinase 2 (Nek2)
Without Binding to the Back Pocket and Reveal a Nonlinear
Structure-Activity Relationship, Journal of Medicinal Chemistry
54(6):1626-1639, Mar. 2011. cited by applicant .
Notice of Defects in Patent Application No. 234091 mailed Aug. 21,
2016, issued in Israeli Application No. 234091, filed Feb. 14,
2013, 8 pages. cited by applicant.
|
Primary Examiner: Stockton; Laura L.
Attorney, Agent or Firm: Christensen O'Connor Johnson
Kindness PLLC
Government Interests
STATEMENT REGARDING FEDERALLY SPONSORED RESEARCH OR DEVELOPMENT
The research described herein was supported in part by funds from
the U.S. Government (NIH SBIR grant R44AI056525 and Grant no.
R01AI093387) and the U.S. Government has certain rights in the
invention.
Parent Case Text
This application is a .sctn.371 National Phase Application of
International Application No. PCT/US2013/026173 filed Feb. 14,
2013, which claims the benefit of priority to U.S. Provisional
Application Ser. No. 61/600,036, filed Feb. 17, 2012, entitled
"ANTIVIRAL DRUGS FOR TREATMENT OF ARENAVIRUS INFECTION," to
Dongcheng Dai, James R. Burgeson, Sean M. Amberg and Dennis E.
Hruby.
Claims
What is claimed is:
1. A compound of Formula I or a pharmaceutically acceptable salt
thereof: ##STR00100## wherein, E is N, J is N, K is C, G, M, Q, and
L are C--R, wherein R is hydrogen, X is C-D-A-Ar.sup.2, wherein D-A
is R.sup.7C.dbd.CR.sup.8, wherein R.sup.7 and R.sup.8 are hydrogen,
Ar.sup.1 is phenyl substituted with an alkoxy group, and Ar.sup.2
is phenyl substituted with a substituent selected from the group
consisting of alkyl, substituted alkyl, haloalkyl, hydroxyalkyl,
cycloalkyl, substituted cycloalkyl, alkenyl, alkoxy, substituted
alkoxy, heterocyclic, substituted heterocyclic, carboxyl,
carboxylalkyl, and cyano.
2. The compound of claim 1, wherein R.sup.7C.dbd.CR.sup.8 has a cis
configuration.
3. The compound of claim 1 selected from the group consisting of:
5-[(Z)-2-(4-tert-butylphenyl)vinyl]-1-(4-isopropoxyphenyl)-benzimidazole
and
2-[4-[(Z)-2-[1-(4-isopropoxyphenyl)benzimidazol-5-yl]vinyl]phenyl]-pr-
opan-2-ol.
4. A pharmaceutical composition comprising a pharmaceutically
acceptable carrier or excipient and a compound of claim 1 or a
pharmaceutically acceptable salt thereof.
5. The composition of claim 4, wherein R.sup.7C.dbd.CR.sup.8 has a
cis configuration.
6. The composition of claim 4, wherein the compound is selected
from the group consisting of:
5-[(Z)-2-(4-tert-butylphenyl)vinyl]-1-(4-isopropoxyphenyl)-benzimidazole
and
2-[4-[(Z)-2-[1-(4-isopropoxyphenyl)benzimidazol-5-yl]vinyl]phenyl]-pr-
opan-2-ol.
7. A method for relieving or causing the regression of a viral
infection, comprising administering in a therapeutically effective
amount to a mammal in need thereof, a compound of claim 1 or a
pharmaceutically acceptable salt thereof.
8. The method of claim 7, wherein R.sup.7C.dbd.CR.sup.8 has a cis
configuration.
9. The method of claim 7, wherein said compound is selected from
the group consisting of:
5-[(Z)-2-(4-tert-butylphenyl)vinyl]-1-(4-isopropoxyphenyl)-benzimidazole
and
2-[4-[(Z)-2-[1-(4-isopropoxyphenyl)benzimidazol-5-yl]vinyl]phenyl]-pr-
opan-2-ol.
10. The method of claim 7, wherein the mammal is a human.
11. The method of claim 7, wherein the viral infection is an
Arenavirus infection.
12. The method of claim 11, wherein the Arenavirus is selected from
the group consisting of Lassa, Junin, Machupo, Guanarito, Sabia,
Whitewater Arroyo, Chapare, LCMV, and LCMV-like viruses selected
from the group consisting of Dandenong, Tacaribe, and Pichinde.
13. The method of claim 7, which further comprises
co-administration of at least one agent selected from the group
consisting of antiviral agent, vaccine, and interferon.
14. The compound of claim 1, wherein R.sup.7C.dbd.CR.sup.8 has a
trans configuration.
15. The compound of claim 1, wherein said compound is selected from
the group consisting of:
1-(4-ethoxyphenyl)-5-[(E)-2-(4-ethylphenyl)vinyl]benzimidazole;
1-(4-ethoxyphenyl)-5-[(Z)-2-(4-ethylphenyl)vinyl]benzimidazole;
5-[(E)-2-(4-isopropylphenyl)vinyl]-1-(4-methoxyphenyl)benzimidazole;
5-[(E)-2-(4-tert-butylphenyl)vinyl]-1-(4-ethoxyphenyl)-benzimidazole;
5-[(Z)-2-(4-tert-butylphenyl)vinyl]-1-(4-ethoxyphenyl)benzimidazole;
5-[(E)-2-(4-tert-butylphenyl)vinyl]-1-(4-isopropoxyphenyl)benzimidazole;
5-[(Z)-2-(4-tert-butylphenyl)vinyl]-1-(4-isopropoxyphenyl)benzimidazole;
5-[(E)-2-(4-ethylphenyl)vinyl]-1-(4-isopropoxyphenyl)benzimidazole;
5-[(Z)-2-(4-ethylphenyl)vinyl]-1-(4-isopropoxyphenyl)benzimidazole;
1-(4-ethoxyphenyl)-5-[(E)-2-[4-(trifluoromethoxy)phenyl]vinyl]benzimidazo-
le;
1-(4-ethoxyphenyl)-5-[(Z)-2-[4-(trifluoromethoxy)phenyl]vinyl]benzimid-
azole;
1-(4-ethoxyphenyl)-5-[(E)-2-[4-(trifluoromethyl)phenyl]vinyl]benzim-
idazole;
1-(4-ethoxyphenyl)-5-[(Z)-2-[4-(trifluoromethyl)phenyl]vinyl]benz-
imidazole;
1-(4-tert-butoxyphenyl)-5-[(E)-2-(4-ethylphenyl)-vinyl]benzimid-
azole;
1-(4-tert-butoxyphenyl)-5-[(Z)-2-(4-ethylphenyl)-vinyl]benzimidazol-
e;
1-(4-tert-butoxyphenyl)-5-[(E)-2-(4-tert-butylphenyl)vinyl]benzimidazol-
e;
1-(4-tert-butoxyphenyl)-5-[(Z)-2-(4-tert-butylphenyl)vinyl]benzimidazol-
e; methyl
4-[(Z)-2-[1-(4-isopropoxyphenyl)benzimidazol-5-yl]vinyl]benzoate- ;
2-[4-[(Z)-2-[1-(4-isopropoxyphenyl)benzimidazol-5-yl]vinyl]phenyl]propan-
-2-ol;
5-[(Z)-2-[4-(1-fluoro-1-methyl-ethyl)phenyl]vinyl]-1-(4-isopropoxyp-
henyl)benzimidazole;
5-[(Z)-2-(4-isopropenylphenyl)vinyl]-1-(4-isopropoxyphenyl)benzimidazole;
5-[4-[(Z)-2-[1-(4-isopropoxyphenyl)benzimidazol-5-yl]vinyl]phenyl]nonan-5-
-ol;
1-(4-isopropoxyphenyl)-5-[(Z)-2-[4-(2,2,2-trifluoro-1,1-dimethyl-ethy-
l)phenyl]vinyl]benzimidazole;
3-[4-[(Z)-2-[1-(4-isopropoxyphenyl)benzimidazol-5-yl]vinyl]phenyl]propana-
l; 4-[(Z)-2-[1-(4-isopropoxyphenyl)benzimidazol-5-yl]vinyl]benzoic
acid;
1,1,1-trifluoro-2-[4-[(Z)-2-[1-(4-isopropoxyphenyl)benzimidazol-5-yl]viny-
l]phenyl]propan-2-ol;
1,1,1,3,3,3-hexafluoro-2-[4-[(Z)-2-[1-(4-isopropoxyphenyl)benzimidazol-5--
yl]vinyl]phenyl]propan-2-ol;
1-[4-[(Z)-2-[1-(4-isopropoxyphenyl)benzimidazol-5-yl]vinyl]phenyl]cyclopr-
opanol;
4-[(Z)-2-[1-(4-isopropoxyphenyl)benzimidazol-5-yl]vinyl]benzonitri-
le;
2-[4-[(Z)-2-[1-(4-isopropoxyphenyl)benzimidazol-5-yl]vinyl]phenyl]buta-
n-2-ol;
1-[4-[(Z)-2-[1-(4-isopropoxyphenyl)benzimidazol-5-yl]vinyl]phenyl]-
ethanol;
1-[4-[(Z)-2-[1-(4-isopropoxyphenyl)benzimidazol-5-yl]vinyl]phenyl-
]cyclobutanol;
3-[4-[(Z)-2-[1-(4-isopropoxyphenyl)benzimidazol-5-yl]vinyl]phenyl]oxetan--
3-ol;
1-[4-[(Z)-2-[1-(4-isopropoxyphenyl)benzimidazol-5-yl]vinyl]phenyl]cy-
clopropanamine;
2-hydroxy-2-[4-[(Z)-2-[1-(4-isopropoxyphenyl)benzimidazol-5-yl]vinyl]phen-
yl]propanoic acid;
1-[4-[(Z)-2-[1-(4-isopropoxyphenyl)benzimidazol-5-yl]vinyl]phenyl]cyclope-
ntanol;
1-[4-[(Z)-2-[1-(4-isopropoxyphenyl)benzimidazol-5-yl]vinyl]phenyl]-
cyclohexanol;
3-[4-[(Z)-2-[1-(4-isopropoxyphenyl)benzimidazol-5-yl]vinyl]phenyl]azetidi-
n-3-ol;
4-[4-[(Z)-2-[1-(4-isopropoxyphenyl)benzimidazol-5-yl]vinyl]phenyl]-
tetrahydropyran-4-ol;
2-[4-[(Z)-2-[1-(4-isopropoxyphenyl)benzimidazol-5-yl]vinyl]phenyl]propan--
2-amine; and
2-[4-[(Z)-2-[1-(4-ethoxyphenyl)benzimidazol-5-yl]vinyl]phenyl]propan-2-ol-
.
16. The composition of claim 4, wherein R.sup.7C.dbd.CR.sup.8 has a
trans configuration.
17. The composition of claim 4, wherein said compound is selected
from the group consisting of:
1-(4-ethoxyphenyl)-5-[(E)-2-(4-ethylphenyl)vinyl]benzimidazole;
1-(4-ethoxyphenyl)-5-[(Z)-2-(4-ethylphenyl)vinyl]benzimidazole;
5-[(E)-2-(4-isopropylphenyl)vinyl]-1-(4-methoxyphenyl)benzimidazole;
5-[(E)-2-(4-tert-butylphenyl)vinyl]-1-(4-ethoxyphenyl)-benzimidazole;
5-[(Z)-2-(4-tert-butylphenyl)vinyl]-1-(4-ethoxyphenyl)benzimidazole;
5-[(E)-2-(4-tert-butylphenyl)vinyl]-1-(4-isopropoxyphenyl)benzimidazole;
5-[(Z)-2-(4-tert-butylphenyl)vinyl]-1-(4-isopropoxyphenyl)benzimidazole;
5-[(E)-2-(4-ethylphenyl)vinyl]-1-(4-isopropoxyphenyl)benzimidazole;
5-[(Z)-2-(4-ethylphenyl)vinyl]-1-(4-isopropoxyphenyl)benzimidazole;
1-(4-ethoxyphenyl)-5-[(E)-2-[4-(trifluoromethoxy)phenyl]vinyl]benzimidazo-
le;
1-(4-ethoxyphenyl)-5-[(Z)-2-[4-(trifluoromethoxy)phenyl]vinyl]benzimid-
azole;
1-(4-ethoxyphenyl)-5-[(E)-2-[4-(trifluoromethyl)phenyl]vinyl]benzim-
idazole;
1-(4-ethoxyphenyl)-5-[(Z)-2-[4-(trifluoromethyl)phenyl]vinyl]benz-
imidazole;
1-(4-tert-butoxyphenyl)-5-[(E)-2-(4-ethylphenyl)-vinyl]benzimid-
azole;
1-(4-tert-butoxyphenyl)-5-[(Z)-2-(4-ethylphenyl)-vinyl]benzimidazol-
e;
1-(4-tert-butoxyphenyl)-5-[(E)-2-(4-tert-butylphenyl)vinyl]benzimidazol-
e;
1-(4-tert-butoxyphenyl)-5-[(Z)-2-(4-tert-butylphenyl)vinyl]benzimidazol-
e; methyl
4-[(Z)-2-[1-(4-isopropoxyphenyl)benzimidazol-5-yl]vinyl]benzoate- ;
2-[4-[(Z)-2-[1-(4-isopropoxyphenyl)benzimidazol-5-yl]vinyl]phenyl]propan-
-2-ol;
5-[(Z)-2-[4-(1-fluoro-1-methyl-ethyl)phenyl]vinyl]-1-(4-isopropoxyp-
henyl)benzimidazole;
5-[(Z)-2-(4-isopropenylphenyl)vinyl]-1-(4-isopropoxyphenyl)benzimidazole;
5-[4-[(Z)-2-[1-(4-isopropoxyphenyl)benzimidazol-5-yl]vinyl]phenyl]nonan-5-
-ol;
1-(4-isopropoxyphenyl)-5-[(Z)-2-[4-(2,2,2-trifluoro-1,1-dimethyl-ethy-
l)phenyl]vinyl]benzimidazole;
3-[4-[(Z)-2-[1-(4-isopropoxyphenyl)benzimidazol-5-yl]vinyl]phenyl]propana-
l; 4-[(Z)-2-[1-(4-isopropoxyphenyl)benzimidazol-5-yl]vinyl]benzoic
acid;
1,1,1-trifluoro-2-[4-[(Z)-2-[1-(4-isopropoxyphenyl)benzimidazol-5-yl]viny-
l]phenyl]propan-2-ol;
1,1,1,3,3,3-hexafluoro-2-[4-[(Z)-2-[1-(4-isopropoxyphenyl)benzimidazol-5--
yl]vinyl]phenyl]propan-2-ol;
1-[4-[(Z)-2-[1-(4-isopropoxyphenyl)benzimidazol-5-yl]vinyl]phenyl]cyclopr-
opanol;
4-[(Z)-2-[1-(4-isopropoxyphenyl)benzimidazol-5-yl]vinyl]benzonitri-
le;
2-[4-[(Z)-2-[1-(4-isopropoxyphenyl)benzimidazol-5-yl]vinyl]phenyl]buta-
n-2-ol;
1-[4-[(Z)-2-[1-(4-isopropoxyphenyl)benzimidazol-5-yl]vinyl]phenyl]-
ethanol;
1-[4-[(Z)-2-[1-(4-isopropoxyphenyl)benzimidazol-5-yl]vinyl]phenyl-
]cyclobutanol;
3-[4-[(Z)-2-[1-(4-isopropoxyphenyl)benzimidazol-5-yl]vinyl]phenyl]oxetan--
3-ol;
1-[4-[(Z)-2-[1-(4-isopropoxyphenyl)benzimidazol-5-yl]vinyl]phenyl]cy-
clopropanamine;
2-hydroxy-2-[4-[(Z)-2-[1-(4-isopropoxyphenyl)benzimidazol-5-yl]vinyl]phen-
yl]propanoic acid;
1-[4-[(Z)-2-[1-(4-isopropoxyphenyl)benzimidazol-5-yl]vinyl]phenyl]cyclope-
ntanol;
1-[4-[(Z)-2-[1-(4-isopropoxyphenyl)benzimidazol-5-yl]vinyl]phenyl]-
cyclohexanol;
3-[4-[(Z)-2-[1-(4-isopropoxyphenyl)benzimidazol-5-yl]vinyl]phenyl]azetidi-
n-3-ol;
4-[4-[(Z)-2-[1-(4-isopropoxyphenyl)benzimidazol-5-yl]vinyl]phenyl]-
tetrahydropyran-4-ol;
2-[4-[(Z)-2-[1-(4-isopropoxyphenyl)benzimidazol-5-yl]vinyl]phenyl]propan--
2-amine; and
2-[4-[(Z)-2-[1-(4-ethoxyphenyl)benzimidazol-5-yl]vinyl]phenyl]propan-2-ol-
.
18. The method of claim 7, wherein R.sup.7C.dbd.CR.sup.8 has a
trans configuration.
19. The method of claim 7, wherein said compound is selected from
the group consisting of:
1-(4-ethoxyphenyl)-5-[(E)-2-(4-ethylphenyl)vinyl]benzimidazole;
1-(4-ethoxyphenyl)-5-[(Z)-2-(4-ethylphenyl)vinyl]benzimidazole;
5-[(E)-2-(4-isopropylphenyl)vinyl]-1-(4-methoxyphenyl)benzimidazole;
5-[(E)-2-(4-tert-butylphenyl)vinyl]-1-(4-ethoxyphenyl)-benzimidazole;
5-[(Z)-2-(4-tert-butylphenyl)vinyl]-1-(4-ethoxyphenyl)benzimidazole;
5-[(E)-2-(4-tert-butylphenyl)vinyl]-1-(4-isopropoxyphenyl)benzimidazole;
5-[(Z)-2-(4-tert-butylphenyl)vinyl]-1-(4-isopropoxyphenyl)benzimidazole;
5-[(E)-2-(4-ethylphenyl)vinyl]-1-(4-isopropoxyphenyl)benzimidazole;
5-[(Z)-2-(4-ethylphenyl)vinyl]-1-(4-isopropoxyphenyl)benzimidazole;
1-(4-ethoxyphenyl)-5-[(E)-2-[4-(trifluoromethoxy)phenyl]vinyl]benzimidazo-
le;
1-(4-ethoxyphenyl)-5-[(Z)-2-[4-(trifluoromethoxy)phenyl]vinyl]benzimid-
azole;
1-(4-ethoxyphenyl)-5-[(E)-2-[4-(trifluoromethyl)phenyl]vinyl]benzim-
idazole;
1-(4-ethoxyphenyl)-5-[(Z)-2-[4-(trifluoromethyl)phenyl]vinyl]benz-
imidazole;
1-(4-tert-butoxyphenyl)-5-[(E)-2-(4-ethylphenyl)-vinyl]benzimid-
azole;
1-(4-tert-butoxyphenyl)-5-[(Z)-2-(4-ethylphenyl)-vinyl]benzimidazol-
e;
1-(4-tert-butoxyphenyl)-5-[(E)-2-(4-tert-butylphenyl)vinyl]benzimidazol-
e;
1-(4-tert-butoxyphenyl)-5-[(Z)-2-(4-tert-butylphenyl)vinyl]benzimidazol-
e; methyl
4-[(Z)-2-[1-(4-isopropoxyphenyl)benzimidazol-5-yl]vinyl]benzoate- ;
2-[4-[(Z)-2-[1-(4-isopropoxyphenyl)benzimidazol-5-yl]vinyl]phenyl]propan-
-2-ol;
5-[(Z)-2-[4-(1-fluoro-1-methyl-ethyl)phenyl]vinyl]-1-(4-isopropoxyp-
henyl)benzimidazole;
5-[(Z)-2-(4-isopropenylphenyl)vinyl]-1-(4-isopropoxyphenyl)benzimidazole;
5-[4-[(Z)-2-[1-(4-isopropoxyphenyl)benzimidazol-5-yl]vinyl]phenyl]nonan-5-
-ol;
1-(4-isopropoxyphenyl)-5-[(Z)-2-[4-(2,2,2-trifluoro-1,1-dimethyl-ethy-
l)phenyl]vinyl]benzimidazole;
3-[4-[(Z)-2-[1-(4-isopropoxyphenyl)benzimidazol-5-yl]vinyl]phenyl]propana-
l; 4-[(Z)-2-[1-(4-isopropoxyphenyl)benzimidazol-5-yl]vinyl]benzoic
acid;
1,1,1-trifluoro-2-[4-[(Z)-2-[1-(4-isopropoxyphenyl)benzimidazol-5-yl]viny-
l]phenyl]propan-2-ol;
1,1,1,3,3,3-hexafluoro-2-[4-[(Z)-2-[1-(4-isopropoxyphenyl)benzimidazol-5--
yl]vinyl]phenyl]propan-2-ol;
1-[4-[(Z)-2-[1-(4-isopropoxyphenyl)benzimidazol-5-yl]vinyl]phenyl]cyclopr-
opanol;
4-[(Z)-2-[1-(4-isopropoxyphenyl)benzimidazol-5-yl]vinyl]benzonitri-
le;
2-[4-[(Z)-2-[1-(4-isopropoxyphenyl)benzimidazol-5-yl]vinyl]phenyl]buta-
n-2-ol;
1-[4-[(Z)-2-[1-(4-isopropoxyphenyl)benzimidazol-5-yl]vinyl]phenyl]-
ethanol;
1-[4-[(Z)-2-[1-(4-isopropoxyphenyl)benzimidazol-5-yl]vinyl]phenyl-
]cyclobutanol;
3-[4-[(Z)-2-[1-(4-isopropoxyphenyl)benzimidazol-5-yl]vinyl]phenyl]oxetan--
3-ol;
1-[4-[(Z)-2-[1-(4-isopropoxyphenyl)benzimidazol-5-yl]vinyl]phenyl]cy-
clopropanamine;
2-hydroxy-2-[4-[(Z)-2-[1-(4-isopropoxyphenyl)benzimidazol-5-yl]vinyl]phen-
yl]propanoic acid;
1-[4-[(Z)-2-[1-(4-isopropoxyphenyl)benzimidazol-5-yl]vinyl]phenyl]cyclope-
ntanol;
1-[4-[(Z)-2-[1-(4-isopropoxyphenyl)benzimidazol-5-yl]vinyl]phenyl]-
cyclohexanol;
3-[4-[(Z)-2-[1-(4-isopropoxyphenyl)benzimidazol-5-yl]vinyl]phenyl]azetidi-
n-3-ol;
4-[4-[(Z)-2-[1-(4-isopropoxyphenyl)benzimidazol-5-yl]vinyl]phenyl]-
tetrahydropyran4-ol;
2-[4-[(Z)-2-[1-(4-isopropoxyphenyl)benzimidazol-5-yl]vinyl]phenyl]propan--
2-amine; and
2-[4-[(Z)-2-[1-(4-ethoxyphenyl)benzimidazol-5-yl]vinyl]phenyl]propan-2-ol-
.
Description
FIELD OF THE INVENTION
This invention relates to the use of benzimidazole derivatives and
analogs, as well as compositions containing the same, for the
treatment or prophylaxis of viral diseases associated with the
arenavirus family such as Lassa fever, Argentine hemorrhagic fever,
Bolivian hemorrhagic fever, and Venezuelan hemorrhagic fever.
BACKGROUND OF THE INVENTION
Viral hemorrhagic fever is a serious illness characterized by
extensive vascular damage and bleeding diathesis, fever, and
multiple organ involvement. Many different viruses can cause this
syndrome, each with its own animal reservoir, mode of transmission,
fatality rate, and clinical outcome in humans. These viruses are
distributed throughout four virus families, the Arenaviridae,
Bunyaviridae, Filoviridae, and Flaviviridae. Several of these
viruses generate significant morbidity and mortality and can be
highly infectious by aerosol dissemination, promoting concern about
weaponization (for an overview, see 3). In 1999, the Centers for
Disease Control and Prevention (CDC) identified and categorized
potential biological terrorism agents as part of a Congressional
initiative to upgrade bioterrorism response capabilities (30).
Filoviruses and arenaviruses were designated as Category A, defined
as those pathogens with the highest potential impact on public
health and safety, potential for large-scale dissemination,
capability for civil disruption, and greatest unmet need for public
health preparedness. The National Institute of Allergy and
Infectious Diseases (NIAID) has since expanded the Category A list
by adding several hemorrhagic bunyaviruses and flaviviruses (27).
In addition, the Working Group on Civilian Biodefense described
several hemorrhagic fever viruses, including Lassa, as those with
the greatest risk for use as biological weapons and recommended the
pursuit of new antiviral therapies (3).
Prevention and treatment options for hemorrhagic fever viruses are
limited. With the exception of an effective vaccine for yellow
fever, no licensed vaccines or FDA-approved antiviral drugs are
available. Intravenous ribavirin has been used with some success to
treat arenaviruses and bunyaviruses, although its use has
significant limitations (see below). In addition, there have been
recent reports of promising vaccines for Ebola (19) and Lassa (16).
Although a successful vaccine could be a critical component of an
effective biodefense, the typical delay to onset of immunity,
potential side-effects, cost, and logistics associated with
large-scale civilian vaccinations against a low-risk threat agent
suggest that a comprehensive biodefense include a separate
rapid-response element. Thus there remains an urgent need to
develop safe and effective products to protect against potential
biological attack.
Lassa fever virus is a member of the Arenaviridae family, a family
of enveloped RNA viruses (4). Arenavirus infection in rodents, the
natural host animal, is usually chronic and asymptomatic. Several
arenaviruses can cause severe hemorrhagic fever in humans,
including Lassa, Machupo, Guanarito, and Junin viruses.
Transmission to humans can result from direct contact with infected
rodents or their habitat, through aerosolized rodent secretions, or
through contact with the body fluids of an infected person.
Although arenaviruses are found world-wide, most of the viral
species are geographically localized to a particular region,
reflecting the range of the specific rodent host involved. The
Arenaviridae family contains a single genus (Arenavirus) that is
divided into two major lineages based on phylogenetic and
serological examination. Lassa fever is a member of the Old World
arenaviruses; the New World arenaviruses can be further divided
into three clades (A-C), one of which (clade B) contains several of
the pathogenic, Category A hemorrhagic fever viruses.
Lassa fever is endemic in West Africa, particularly the countries
of Guinea, Liberia, Sierra Leone, and Nigeria. Human infections are
estimated at 100,000 to 500,000 per year (25). Initial symptoms of
Lassa fever appear about 10 days after exposure, and include fever,
sore throat, chest and back pain, cough, vomiting, diarrhea,
conjunctivitis, facial swelling, proteinuria, and mucosal bleeding.
Clinical diagnosis is often difficult due to the nonspecific nature
of the symptoms. In fatal cases, continuing progression of symptoms
leads to the onset of shock. Among hospitalized patients, the
mortality rate is 15-20% (23), although the fatality rate for some
outbreaks has been reported higher than 50% (14). Infectious virus
can remain in the bodily fluids of convalescent patients for
several weeks (34). Transient or permanent deafness is common in
survivors (10) and appears to be just as frequent in mild or
asymptomatic cases as it is in severe cases (22). Lassa fever is
occasionally imported into Europe (17) and the U.S., most recently
in 2004 (7). The risk of the virus becoming endemic outside of West
Africa appears low due to the nature of the rodent host. However,
the combination of increased world travel and viral adaptation
presents a finite possibility of a virus "jumping" into a new
ecosystem. For example, West Nile virus was introduced into the New
York City area in 1999 and is now endemic in the U.S.
A small trial conducted in Sierra Leone in the 1980s demonstrated
that mortality from Lassa fever can be reduced in high-risk
patients by treatment with intravenous ribavirin, a nucleoside
analog that exhibits nonspecific antiviral activity (24). Ribavirin
has been shown to inhibit Lassa fever viral RNA synthesis in vitro
(18). Although of limited availability, intravenous ribavirin is
available for compassionate use under an investigational new drug
protocol. It is also available in oral form for treating hepatitis
C (in combination with interferon), although less is known about
the efficacy of orally-administered ribavirin for treating Lassa
fever. As a nucleoside analog, ribavirin can interfere with DNA and
RNA replication, and in fact teratogenicity and embryo lethality
have been seen in several animal species. It is therefore
contraindicated for pregnant patients (a pregnancy category X
drug). In addition, it is associated with a dose-related hemolytic
anemia; although the anemia is reversible, anemia-associated
cardiac and pulmonary events occur in approximately 10% of
hepatitis C patients receiving ribavirin-interferon therapy.
Intravenous ribavirin is expensive, and daily I.V. administration
to a large civilian population in an emergency would be a
cumbersome approach. It is possible that further study may
eventually support the use of oral interferon, either alone or in
combination with other antivirals, for treatment of Lassa fever.
Successful antiviral therapy often involves administering a
combination of pharmaceuticals, such as the treatment of chronic
hepatitis C with interferon and ribavirin, and treatment of AIDS
with highly active antiretroviral therapy (HAART), a cocktail of
three different drugs. Because of the high mutation rate and the
quasispecies nature associated with viruses, treatment with
compounds that act on multiple, distinct targets can be more
successful than treatment with a single drug.
The arenavirus genome consists of two segments of single-stranded
RNA, each of which codes for two genes in opposite orientations
(referred to as ambisense). The larger of the two segments, the L
RNA (7.2 kb), encodes the L and Z proteins. The L protein is the
RNA dependent RNA polymerase, and the Z protein is a small
zinc-binding RING finger protein which is involved in virus budding
(29). The S RNA (3.4 kb) encodes the nucleoprotein (NP) and the
envelope glycoprotein precursor (GPC).
The envelope glycoprotein is embedded in the lipid bilayer that
surrounds the viral nucleocapsid. The characteristics of the
arenavirus glycoprotein suggest that it can be classified as a Type
I envelope (15), which is typified by influenza hemagglutinin and
found also in retroviruses, paramyxoviruses, coronaviruses, and
filoviruses (8). Type I envelopes function both to attach the virus
to specific host cell receptors and also to mediate fusion of the
viral membrane with the host membrane, thereby depositing the viral
genome inside the target cell. Cotranslational translocation of the
envelope protein across the membrane of the endoplasmic reticulum
is facilitated by an N-terminal signal peptide that is subsequently
removed by a signal peptidase. Post-translational proteolysis
further processes the envelope into an N-terminal subunit (denoted
GP1 for arenaviruses), which contains the receptor binding
determinants, and a C-terminal transmembrane subunit (GP2), which
is capable of undergoing the dramatic conformational rearrangements
that are associated with membrane fusion. The two subunits remain
associated with one another and assemble into trimeric complexes of
this heterodimer, although arenavirus envelope glycoproteins have
been reported to have a tetrameric structure (5). Mature envelope
glycoproteins accumulate at the site of viral budding, such as the
plasma membrane, and thus are embedded within the envelope that the
virus acquires as viral budding occurs.
The signal peptide of the arenavirus glycoprotein is quite unusual
(12); at 58 amino acids in length, it is larger than most signal
peptides (13). In addition, it remains associated with the envelope
and with mature virions, and appears to be important for the
subsequent GP1-GP2 processing (11). This processing is essential
for envelope function and is mediated by the cellular subtilase
SKI-1/S1P (1, 20, 21). The envelope glycoprotein interacts directly
with the host cellular receptor to facilitate viral entry into the
target cell. The receptor for Old World arenaviruses is
.alpha.-dystroglycan (6), a major component of the dystrophin
glycoprotein complex. The New World arenaviruses appear to have
diverged from this receptor, as only the clade C viruses use
.alpha.-dystroglycan as a major receptor (32). The receptor for the
New World clades A and B arenaviruses has not yet been
identified.
SUMMARY OF THE INVENTION
The present invention provides a compound having the following
general Formula I or a pharmaceutically acceptable salt
thereof:
##STR00001##
wherein, X is C-D-A-Ar.sup.2 and L is independently N or C--R; or X
is independently N or C--R and L is C-D-A-Ar.sup.2; wherein D-A is
independently selected from the group consisting of:
CR.sup.1R.sup.2--NR', S--CR.sup.1R.sup.2, O--CR.sup.1R.sup.2,
R.sup.3R.sup.4C--CR.sup.5R.sup.6, R.sup.7C.dbd.CR.sup.8, and
C.ident.C; and E, G, M, and Q are independently N or C--R; J and K
are independently N or C;
R is selected from the group consisting of hydrogen, substituted or
unsubstituted alkyl, haloalkyl, alkenyl, alkynyl, cycloalkyl,
heterocycloalkyl, arylalkyl, aryl, heteroaryl, hydroxy, alkyloxy,
aryloxy, heteroaryloxy, acyloxy, arylacyloxy, heteroarylacyloxy,
alkylsulfonyloxy, arylsulfonyloxy, thio, alkylthio, arylthio,
amino, alkylamino, dialkylamino, cycloalkylamino,
heterocycloalkylamino, arylamino, heteroarylamino, acylamino,
arylacylamino, heteroarylacylamino, alkylsulfonylamino,
arylsulfonylamino, acyl, arylacyl, heteroarylacyl, alkylsulfinyl,
arylsulfinyl, heteroarylsulfinyl, hydroxysulfonyl, alkylsulfonyl,
arylsulfonyl, heteroarylsulfonyl, aminosulfonyl, substituted
aminosulfonyl, carboxy, alkoxycarbonyl, cycloalkyloxycarbonyl,
aryloxycarbonyl, carbamoyl, substituted carbamoyl, halogen, cyano,
isocyano and nitro;
R' is as follows: (a) R' is selected from the group consisting of:
hydrogen, substituted or unsubstituted alkyl, haloalkyl, alkenyl,
alkynyl, cycloalkyl, heterocycloalkyl, arylalkyl, aryl, heteroaryl,
hydroxy, alkyloxy, aryloxy, heteroaryloxy, acyloxy, arylacyloxy,
heteroarylacyloxy, alkylsulfonyloxy, arylsulfonyloxy, thio,
alkylthio, arylthio, amino, alkylamino, dialkylamino,
cycloalkylamino, heterocycloalkylamino, arylamino, heteroarylamino,
acylamino, arylacylamino, heteroarylacylamino, alkylsulfonylamino,
arylsulfonylamino, acyl, arylacyl, heteroarylacyl, alkylsulfinyl,
arylsulfinyl, heteroarylsulfinyl, hydroxysulfonyl, alkylsulfonyl,
arylsulfonyl, heteroarylsulfonyl, aminosulfonyl, substituted
aminosulfonyl, carboxy, alkoxycarbonyl, cycloalkyloxycarbonyl,
aryloxycarbonyl, carbamoyl, substituted carbamoyl; (b) R' together
with the nitrogen atom it is attached to, some carbons of Ar.sup.2,
form a substituted or unsubstituted ring, which optionally includes
one or more heteroatoms in the ring; (c) R' together with the
nitrogen atom it is attached to, the carbon atom R.sup.1 and
R.sup.2 are attached to, R.sup.1 or R.sup.2, form a substituted or
unsubstituted ring, which optionally includes one or more
heteroatoms in the ring; or d) R' together with the nitrogen atom
it is attached to, the carbon atom R.sup.1 and R.sup.2 are attached
to, some carbons of the aromatic ring next to this carbon, form a
substituted or unsubstituted ring, which optionally includes one or
more heteroatoms in the ring;
R.sup.1 and R.sup.2 are as follows: (a) independently selected from
the group consisting of hydrogen, halogen, haloalkyl, alkyl,
alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, arylalkyl, aryl,
heteroaryl, acyl, arylacyl, heteroarylacyl, alkylsulfinyl,
arylsulfinyl, heteroarylsulfinyl, hydroxysulfonyl, alkylsulfonyl,
arylsulfonyl, heteroarylsulfonyl, aminosulfonyl, substituted
aminosulfonyl, alkoxycarbonyl, cycloalkyloxycarbonyl,
aryloxycarbonyl, carbamoyl and substituted carbamoyl; (b) R.sup.1
and R.sup.2 together with the carbon atom they are attached to form
a substituted or unsubstituted ring, which optionally includes one
or more heteroatoms in the ring; (c) R.sup.1 or R.sup.2 together
with the carbon atom it is attached to, the sulfur or oxygen atom
next to this carbon, some carbons of the aromatic ring next to this
atom, form a substituted or unsubstituted ring, which optionally
includes one or more heteroatoms in the ring; (d) when D-A is
CR.sup.1R.sup.2--NR, R.sup.1 or R.sup.2 together with the carbon
atom it is attached to, some carbons of the aromatic ring next to
this carbon, form a substituted or unsubstituted ring, which
optionally includes one or more heteroatoms in the ring; or (e)
R.sup.1 or R.sup.2 together with the carbon atom it is attached to,
the nitrogen atom when D-A is CR.sup.1R.sup.2--NR, some carbons of
Ar.sup.2, form a substituted or unsubstituted ring, which
optionally includes one or more heteroatoms in the ring;
R.sup.3, R.sup.4, R.sup.5, R.sup.6 are as follows: (a) R.sup.3,
R.sup.4, R.sup.5, R.sup.6 are independently selected from the group
consisting of: hydrogen, halogen, haloalkyl, alkyl, alkenyl,
alkynyl, cycloalkyl, heterocycloalkyl, arylalkyl, aryl, heteroaryl,
acyl, arylacyl, heteroarylacyl, alkylsulfinyl, arylsulfinyl,
heteroarylsulfinyl, hydroxysulfonyl, alkylsulfonyl, arylsulfonyl,
heteroarylsulfonyl, aminosulfonyl, substituted aminosulfonyl,
alkoxycarbonyl, cycloalkyloxycarbonyl, aryloxycarbonyl, carbamoyl
and substituted carbamoyl; (b) R.sup.3 and R.sup.4 together with
the carbon atom they are attached to form a substituted or
unsubstituted ring, which optionally includes one or more
heteroatoms in the ring; (c) R.sup.3 or R.sup.4 together with the
carbon atom it is attached to, R.sup.5 or R.sup.6 together with the
carbon atom it is attached to, form a substituted or unsubstituted
ring, which optionally includes one or more heteroatoms in the
ring; (d) R.sup.3 or R.sup.4 together with the carbon atom it is
attached to, the carbon atom R.sup.5 or R.sup.6 is attached to,
some carbons of Ar.sup.2, form a substituted or unsubstituted ring,
which optionally includes one or more heteroatoms in the ring; (e)
R.sup.3 or R.sup.4 together with the carbon atom it is attached to,
some carbons of the aromatic ring next to this carbon, form a
substituted or unsubstituted ring, which optionally includes one or
more heteroatoms in the ring; (f) R.sup.5 and R.sup.6 together with
the carbon atom they are attached to form a substituted or
unsubstituted ring, which optionally includes one or more
heteroatoms in the ring; (g) R.sup.5 or R.sup.6 together with the
carbon atom it is attached to, some carbons of Ar.sup.2, form a
substituted or unsubstituted ring, which optionally includes one or
more heteroatoms in the ring; or (h) R.sup.5 or R.sup.6 together
with the carbon atom it is attached to, the carbon atom R.sup.3 or
R.sup.4 is attached to, some carbons of the aromatic ring next to
this carbon, form a substituted or unsubstituted ring, which
optionally includes one or more heteroatoms in the ring;
R.sup.7 and R.sup.8 are as follows: (a) R.sup.7 and R.sup.8 are
independently selected from the group consisting of hydrogen,
substituted or unsubstituted alkyl, haloalkyl, alkenyl, alkynyl,
cycloalkyl, heterocycloalkyl, arylalkyl, aryl, heteroaryl, hydroxy,
alkyloxy, aryloxy, heteroaryloxy, acyloxy, arylacyloxy,
heteroarylacyloxy, alkylsulfonyloxy, arylsulfonyloxy, thio,
alkylthio, arylthio, amino, alkylamino, dialkylamino,
cycloalkylamino, heterocycloalkylamino, arylamino, heteroarylamino,
acylamino, arylacylamino, heteroarylacylamino, alkylsulfonylamino,
arylsulfonylamino, acyl, arylacyl, heteroarylacyl, alkylsulfinyl,
arylsulfinyl, heteroarylsulfinyl, hydroxysulfonyl, alkylsulfonyl,
arylsulfonyl, heteroarylsulfonyl, aminosulfonyl, substituted
aminosulfonyl, carboxy, alkoxycarbonyl, cycloalkyloxycarbonyl,
aryloxycarbonyl, carbamoyl, substituted carbamoyl, halogen, cyano,
isocyano and nitro; (b) R.sup.7 and R.sup.8 together with the
carbon atoms they are attached to form a substituted or
unsubstituted ring, which optionally includes one or more
heteroatoms in the ring; (c) R.sup.7 together with the carbon atom
it is attached to, some carbons of the aromatic ring next to this
carbon, form a substituted or unsubstituted ring, which optionally
includes one or more heteroatoms in the ring; (d) R.sup.7 together
with the carbon atom it is attached to, the carbon atom R.sup.8 is
attached to, some carbons of Ar.sup.2, form a substituted or
unsubstituted ring, which optionally includes one or more
heteroatoms in the ring; (e) R.sup.8 together with the carbon atom
it is attached to, some carbons of Ar.sup.2, form a substituted or
unsubstituted ring, which optionally includes one or more
heteroatoms in the ring; or (f) R.sup.8 together with the carbon
atom it is attached to, the carbon atom R.sup.7 is attached to,
some carbons of the aromatic ring next to this carbon, form a
substituted or unsubstituted ring, which optionally includes one or
more heteroatoms in the ring; and
Ar.sup.1 and Ar.sup.2 are independently (un)substituted aryl or
heteroaryl.
The present invention also provides a pharmaceutical formulation
comprising the compound of Formula I and one or more
pharmaceutically acceptable ingredient or excipient.
The present invention further provides a method for the treatment
or prophylaxis of a viral infection or disease associated
therewith, comprising administering in a therapeutically effective
amount to a mammal in need thereof, a compound of Formula I or a
pharmaceutically acceptable salt thereof.
The present invention also provides a compound having the following
general Formula II or a pharmaceutically acceptable salt
thereof:
##STR00002##
wherein, E is independently N, N.sup.+--O.sup.-, or C--R; G, L, M,
and Q are independently N or C--R; and J and K are independently N
or C with the proviso that when n=0, E and J cannot both be N;
R is selected from the group consisting of hydrogen, substituted or
unsubstituted alkyl, haloalkyl, alkenyl, alkynyl, cycloalkyl,
heterocycloalkyl, arylalkyl, aryl, heteroaryl, hydroxy, alkyloxy,
aryloxy, heteroaryloxy, acyloxy, arylacyloxy, heteroarylacyloxy,
alkylsulfonyloxy, arylsulfonyloxy, thio, alkylthio, arylthio,
amino, alkylamino, dialkylamino, cycloalkylamino,
heterocycloalkylamino, arylamino, heteroarylamino, acylamino,
arylacylamino, heteroarylacylamino, alkylsulfonylamino,
arylsulfonylamino, acyl, arylacyl, heteroarylacyl, alkylsulfinyl,
arylsulfinyl, heteroarylsulfinyl, hydroxysulfonyl, alkylsulfonyl,
arylsulfonyl, heteroarylsulfonyl, aminosulfonyl, substituted
aminosulfonyl, carboxy, alkoxycarbonyl, cycloalkyloxycarbonyl,
aryloxycarbonyl, carbamoyl, substituted carbamoyl, halogen, cyano,
isocyano and nitro;
R' is as follows: (a) R' is independently selected from the group
consisting of: hydrogen, alkyl, alkenyl, alkynyl, cycloalkyl,
heterocycloalkyl, arylalkyl, aryl, heteroaryl, acyl, arylacyl,
heteroarylacyl, alkylsulfinyl, arylsulfinyl, heteroarylsulfinyl,
hydroxysulfonyl, alkylsulfonyl, arylsulfonyl, heteroarylsulfonyl,
aminosulfonyl, substituted aminosulfonyl, alkoxycarbonyl,
cycloalkyloxycarbonyl, aryloxycarbonyl, carbamoyl and substituted
carbamoyl; (b) R' together with the nitrogen atom it is attached
to, the carbon atom R.sup.1 and R.sup.2 are attached to, R.sup.1 or
R.sup.2, form a substituted or unsubstituted ring, which optionally
includes one or more heteroatoms in the ring; (c) R' together with
the nitrogen atom it is attached to, the carbon atom R.sup.1 and
R.sup.2 are attached to, some carbons of Ar.sup.2, form a
substituted or unsubstituted ring, which optionally includes one or
more heteroatoms in the ring; or (d) R' together with the nitrogen
atom it is attached to, some carbons of the aromatic ring next to
this nitrogen, form a substituted or unsubstituted ring, which
optionally includes one or more heteroatoms in the ring;
R.sup.1 and R.sup.2 are as follows: (a) R.sup.1 and R.sup.2 are
independently selected from the group consisting of hydrogen,
alkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, arylalkyl,
aryl, heteroaryl, acyl, arylacyl, heteroarylacyl, alkylsulfinyl,
arylsulfinyl, heteroarylsulfinyl, hydroxysulfonyl, alkylsulfonyl,
arylsulfonyl, heteroarylsulfonyl, aminosulfonyl, substituted
aminosulfonyl, alkoxycarbonyl, cycloalkyloxycarbonyl,
aryloxycarbonyl, carbamoyl and substituted carbamoyl; (b) R.sup.1
and R.sup.2 together with the carbon atom they are attached to form
a substituted or unsubstituted ring, which optionally include one
or more heteroatoms in the ring; (c) R.sup.1 or R.sup.2 together
with the carbon atom it is attached to, the nitrogen next to this
carbon, and some carbons of the aromatic ring next to this
nitrogen, form a substituted or unsubstituted ring, which
optionally include one or more heteroatoms in the ring; or (d)
R.sup.1 or R.sup.2 together with the carbon atom it is attached to,
some carbons of Ar.sup.2, form a substituted or unsubstituted ring,
which optionally includes one or more heteroatoms in the ring;
n is an integer from 0-4; and
Ar.sup.1 and Ar.sup.2 are independently (un)substituted aryl or
heteroaryl.
The present invention further provides a pharmaceutical formulation
comprising the compound of Formula II and one or more
pharmaceutically acceptable ingredient or excipient.
The present invention also provides a method for the treatment or
prophylaxis of a viral infection or disease associated therewith,
comprising administering in a therapeutically effective amount to a
mammal in need thereof, a compound of Formula II or a
pharmaceutically acceptable salt thereof.
Other objects and advantages of the present invention will become
apparent from the following description and appended claims.
DETAILED DESCRIPTION OF THE INVENTION
The compounds of the invention include compounds which are of the
following general Formula I or a pharmaceutically acceptable salt
thereof:
##STR00003##
wherein, X is C-D-A-Ar.sup.2 and L is independently N or C--R; or X
is independently N or C--R and L is C-D-A-Ar.sup.2; wherein D-A is
independently selected from the group consisting of:
CR.sup.1R.sup.2--NR', S--CR.sup.1R.sup.2, O--CR.sup.1R.sup.2,
R.sup.3R.sup.4C--CR.sup.5R.sup.6, R.sup.7C.dbd.CR.sup.8, and
C.ident.C; and E, G, M, and Q are independently N or C--R; J and K
are independently N or C;
R is selected from the group consisting of hydrogen, substituted or
unsubstituted alkyl, haloalkyl, alkenyl, alkynyl, cycloalkyl,
heterocycloalkyl, arylalkyl, aryl, heteroaryl, hydroxy, alkyloxy,
aryloxy, heteroaryloxy, acyloxy, arylacyloxy, heteroarylacyloxy,
alkylsulfonyloxy, arylsulfonyloxy, thio, alkylthio, arylthio,
amino, alkylamino, dialkylamino, cycloalkylamino,
heterocycloalkylamino, arylamino, heteroarylamino, acylamino,
arylacylamino, heteroarylacylamino, alkylsulfonylamino,
arylsulfonylamino, acyl, arylacyl, heteroarylacyl, alkylsulfinyl,
arylsulfinyl, heteroarylsulfinyl, hydroxysulfonyl, alkylsulfonyl,
arylsulfonyl, heteroarylsulfonyl, aminosulfonyl, substituted
aminosulfonyl, carboxy, alkoxycarbonyl, cycloalkyloxycarbonyl,
aryloxycarbonyl, carbamoyl, substituted carbamoyl, halogen, cyano,
isocyano and nitro;
R' is as follows: (a) R' is selected from the group consisting of:
hydrogen, substituted or unsubstituted alkyl, haloalkyl, alkenyl,
alkynyl, cycloalkyl, heterocycloalkyl, arylalkyl, aryl, heteroaryl,
hydroxy, alkyloxy, aryloxy, heteroaryloxy, acyloxy, arylacyloxy,
heteroarylacyloxy, alkylsulfonyloxy, arylsulfonyloxy, thio,
alkylthio, arylthio, amino, alkylamino, dialkylamino,
cycloalkylamino, heterocycloalkylamino, arylamino, heteroarylamino,
acylamino, arylacylamino, heteroarylacylamino, alkylsulfonylamino,
arylsulfonylamino, acyl, arylacyl, heteroarylacyl, alkylsulfinyl,
arylsulfinyl, heteroarylsulfinyl, hydroxysulfonyl, alkylsulfonyl,
arylsulfonyl, heteroarylsulfonyl, aminosulfonyl, substituted
aminosulfonyl, carboxy, alkoxycarbonyl, cycloalkyloxycarbonyl,
aryloxycarbonyl, carbamoyl, substituted carbamoyl; (b) R' together
with the nitrogen atom it is attached to, some carbons of Ar.sup.2,
form a substituted or unsubstituted ring, which optionally includes
one or more heteroatoms in the ring; (c) R' together with the
nitrogen atom it is attached to, the carbon atom R.sup.1 and
R.sup.2 are attached to, R.sup.1 or R.sup.2, form a substituted or
unsubstituted ring, which optionally includes one or more
heteroatoms in the ring; or d) R' together with the nitrogen atom
it is attached to, the carbon atom R.sup.1 and R.sup.2 are attached
to, some carbons of the aromatic ring next to this carbon, form a
substituted or unsubstituted ring, which optionally includes one or
more heteroatoms in the ring;
R.sup.1 and R.sup.2 are as follows: (a) independently selected from
the group consisting of hydrogen, halogen, haloalkyl, alkyl,
alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, arylalkyl, aryl,
heteroaryl, acyl, arylacyl, heteroarylacyl, alkylsulfinyl,
arylsulfinyl, heteroarylsulfinyl, hydroxysulfonyl, alkylsulfonyl,
arylsulfonyl, heteroarylsulfonyl, aminosulfonyl, substituted
aminosulfonyl, alkoxycarbonyl, cycloalkyloxycarbonyl,
aryloxycarbonyl, carbamoyl and substituted carbamoyl; (b) R.sup.1
and R.sup.2 together with the carbon atom they are attached to form
a substituted or unsubstituted ring, which optionally includes one
or more heteroatoms in the ring; (c) R.sup.1 or R.sup.2 together
with the carbon atom it is attached to, the sulfur or oxygen atom
next to this carbon, some carbons of the aromatic ring next to this
atom, form a substituted or unsubstituted ring, which optionally
includes one or more heteroatoms in the ring; (d) when D-A is
CR.sup.1R.sup.2--NR, R.sup.1 or R.sup.2 together with the carbon
atom it is attached to, some carbons of the aromatic ring next to
this carbon, form a substituted or unsubstituted ring, which
optionally includes one or more heteroatoms in the ring; or (e)
R.sup.1 or R.sup.2 together with the carbon atom it is attached to,
the nitrogen atom when D-A is CR.sup.1R.sup.2--NR, some carbons of
Ar.sup.2, form a substituted or unsubstituted ring, which
optionally includes one or more heteroatoms in the ring;
R.sup.3, R.sup.4, R.sup.5, R.sup.6 are as follows: (a) R.sup.3,
R.sup.4, R.sup.5, R.sup.6 are independently selected from the group
consisting of: hydrogen, halogen, haloalkyl, alkyl, alkenyl,
alkynyl, cycloalkyl, heterocycloalkyl, arylalkyl, aryl, heteroaryl,
acyl, arylacyl, heteroarylacyl, alkylsulfinyl, arylsulfinyl,
heteroarylsulfinyl, hydroxysulfonyl, alkylsulfonyl, arylsulfonyl,
heteroarylsulfonyl, aminosulfonyl, substituted aminosulfonyl,
alkoxycarbonyl, cycloalkyloxycarbonyl, aryloxycarbonyl, carbamoyl
and substituted carbamoyl; (b) R.sup.3 and R.sup.4 together with
the carbon atom they are attached to form a substituted or
unsubstituted ring, which optionally includes one or more
heteroatoms in the ring; (c) R.sup.3 or R.sup.4 together with the
carbon atom it is attached to, R.sup.5 or R.sup.6 together with the
carbon atom it is attached to, form a substituted or unsubstituted
ring, which optionally includes one or more heteroatoms in the
ring; (d) R.sup.3 or R.sup.4 together with the carbon atom it is
attached to, the carbon atom R.sup.5 or R.sup.6 is attached to,
some carbons of Ar.sup.2, form a substituted or unsubstituted ring,
which optionally includes one or more heteroatoms in the ring; (e)
R.sup.3 or R.sup.4 together with the carbon atom it is attached to,
some carbons of the aromatic ring next to this carbon, form a
substituted or unsubstituted ring, which optionally includes one or
more heteroatoms in the ring; (f) R.sup.5 and R.sup.6 together with
the carbon atom they are attached to form a substituted or
unsubstituted ring, which optionally includes one or more
heteroatoms in the ring; (g) R.sup.5 or R.sup.6 together with the
carbon atom it is attached to, some carbons of Ar.sup.2, form a
substituted or unsubstituted ring, which optionally includes one or
more heteroatoms in the ring; or (h) R.sup.5 or R.sup.6 together
with the carbon atom it is attached to, the carbon atom R.sup.3 or
R.sup.4 is attached to, some carbons of the aromatic ring next to
this carbon, form a substituted or unsubstituted ring, which
optionally includes one or more heteroatoms in the ring;
R.sup.7 and R.sup.8 are as follows: (a) R.sup.7 and R.sup.8 are
independently selected from the group consisting of hydrogen,
substituted or unsubstituted alkyl, haloalkyl, alkenyl, alkynyl,
cycloalkyl, heterocycloalkyl, arylalkyl, aryl, heteroaryl, hydroxy,
alkyloxy, aryloxy, heteroaryloxy, acyloxy, arylacyloxy,
heteroarylacyloxy, alkylsulfonyloxy, arylsulfonyloxy, thio,
alkylthio, arylthio, amino, alkylamino, dialkylamino,
cycloalkylamino, heterocycloalkylamino, arylamino, heteroarylamino,
acylamino, arylacylamino, heteroarylacylamino, alkylsulfonylamino,
arylsulfonylamino, acyl, arylacyl, heteroarylacyl, alkylsulfinyl,
arylsulfinyl, heteroarylsulfinyl, hydroxysulfonyl, alkylsulfonyl,
arylsulfonyl, heteroarylsulfonyl, aminosulfonyl, substituted
aminosulfonyl, carboxy, alkoxycarbonyl, cycloalkyloxycarbonyl,
aryloxycarbonyl, carbamoyl, substituted carbamoyl, halogen, cyano,
isocyano and nitro; (b) R.sup.7 and R.sup.8 together with the
carbon atoms they are attached to form a substituted or
unsubstituted ring, which optionally includes one or more
heteroatoms in the ring; (c) R.sup.7 together with the carbon atom
it is attached to, some carbons of the aromatic ring next to this
carbon, form a substituted or unsubstituted ring, which optionally
includes one or more heteroatoms in the ring; (d) R.sup.7 together
with the carbon atom it is attached to, the carbon atom R.sup.8 is
attached to, some carbons of Ar.sup.2, form a substituted or
unsubstituted ring, which optionally includes one or more
heteroatoms in the ring; (e) R.sup.8 together with the carbon atom
it is attached to, some carbons of Ar.sup.2, form a substituted or
unsubstituted ring, which optionally includes one or more
heteroatoms in the ring; or (f) R.sup.8 together with the carbon
atom it is attached to, the carbon atom R.sup.7 is attached to,
some carbons of the aromatic ring next to this carbon, form a
substituted or unsubstituted ring, which optionally includes one or
more heteroatoms in the ring; and
Ar.sup.1 and Ar.sup.2 are independently (un)substituted aryl or
heteroaryl.
Preferably for compounds of Formula I, each of E and J is N; each
of G, M, Q and L is C--R; K is C; and D-A is R.sup.7C.dbd.CR.sup.8,
wherein each of R.sup.7 and R.sup.8 are H and the double bond in
R.sup.7C.dbd.CR.sup.8 has a cis configuration. Also preferably, D-A
is O--CR.sup.1R.sup.2 and each of R.sup.1 and R.sup.2 are H.
Preferred compounds of Formula I also include the compounds of
Formula Ia:
##STR00004##
wherein E, G, J, L, M, Q, K, R.sup.7, R.sup.8, Ar.sup.1 and
Ar.sup.2 are as defined above in Formula I.
Preferably, the compound of Formula I of the present invention is
selected from the group consisting of
1-(4-ethoxyphenyl)-5-[(E)-2-(4-ethylphenyl)vinyl]-benzimidazole;
1-(4-ethoxyphenyl)-5-[(Z)-2-(4-ethylphenyl)vinyl]-benzimidazole;
5-[(E)-2-(4-isopropylphenyl)vinyl]-1-(4-methoxyphenyl)benzimidazole;
5-[(E)-2-(4-tert-butylphenyl)vinyl]-1-(4-ethoxyphenyl)benzimidazole;
5-[(Z)-2-(4-tert-butylphenyl)vinyl]-1-(4-ethoxyphenyl)-benzimidazole;
5-[(E)-2-(4-tert-butylphenyl)vinyl]-1-(4-isopropoxyphenyl)-benzimidazole;
5-[(Z)-2-(4-tert-butylphenyl)vinyl]-1-(4-isopropoxyphenyl)-benzimidazole;
5-[(E)-2-(4-ethylphenyl)vinyl]-1-(4-isopropoxyphenyl)-benzimidazole;
5-[(Z)-2-(4-ethylphenyl)vinyl]-1-(4-isopropoxyphenyl)-benzimidazole;
1-(4-ethoxyphenyl)-5-[(E)-2-[4-(trifluoromethoxy)phenyl]vinyl]benzimidazo-
le;
1-(4-ethoxyphenyl)-5-[(Z)-2-[4-(trifluoromethoxy)-phenyl]vinyl]benzimi-
dazole;
1-(4-ethoxyphenyl)-5-[(E)-2-[4-(trifluoromethyl)phenyl]vinyl]benzi-
midazole;
1-(4-ethoxyphenyl)-5-[(Z)-2-[4-(trifluoromethyl)phenyl]-vinyl]be-
nzimidazole;
1-(4-tert-butoxyphenyl)-5-[(E)-2-(4-ethylphenyl)-vinyl]benzimidazole;
1-(4-tert-butoxyphenyl)-5-[(Z)-2-(4-ethylphenyl)-vinyl]benzimidazole;
1-(4-tert-butoxyphenyl)-5-[(E)-2-(4-tert-butylphenyl)vinyl]-benzimidazole-
;
1-(4-tert-butoxyphenyl)-5-[(Z)-2-(4-tert-butylphenyl)vinyl]benzimidazole-
;
1-(5-ethoxy-2-pyridyl)-5-[(E)-2-(4-ethylphenyl)vinyl]benzimidazole
hydrochloride;
1-(5-ethoxy-2-pyridyl)-5-[(Z)-2-(4-ethylphenyl)vinyl]-benzimidazole
hydrochloride;
5-[(E)-2-(4-tert-butylphenyl)vinyl]-1-(5-ethoxy-2-pyridyl)benzimidazole
hydrochloride;
5-[(Z)-2-(4-tert-butylphenyl)vinyl]-1-(5-ethoxy-2-pyridyl)benzimidazole
hydrochloride;
3-(4-ethoxyphenyl)-6-[(E)-2-(4-ethylphenyl)vinyl]imidazo[4,5-b]pyridine;
3-(4-ethoxyphenyl)-6-[(Z)-2-(4-ethylphenyl)-vinyl]imidazo[4,5-b]pyridine;
6-[(E)-2-(4-isopropylphenyl)vinyl]-3-(4-methoxyphenyl)imidazo[4,5-b]pyrid-
ine;
6-[(Z)-2-(4-isopropylphenyl)vinyl]-3-(4-methoxyphenyl)imidazo[4,5-b]p-
yridine;
3-(4-ethoxyphenyl)-6-[2-(4-ethylphenyl)-ethynyl]imidazo[4,5-b]pyr-
idine; 1-(4-ethoxyphenyl)-5-[2-(4-ethylphenyl)-ethyl]benzimidazole;
3-(4-ethoxyphenyl)-6-[2-(4-ethylphenyl)-ethyl]imidazo[4,5-b]pyridine;
1-(4-ethoxyphenyl)-5-[(4-ethylphenyl)-methoxy]benzimidazole;
5-[(4-isopropylphenyl)methoxy]-1-(4-methoxyphenyl)benzimidazole;
3-(4-ethoxyphenyl)-6-[(4-ethylphenyl)-methoxy]imidazo[4,5-b]pyridine;
6-[(4-isopropyl-phenyl)methoxy]-3-(4-methoxyphenyl)imidazo[4,5-b]pyridine-
;
1-(4-ethoxyphenyl)-5-[(4-ethylphenyl)-methylsulfanyl]benzimidazole;
N-[[1-(4-ethoxyphenyl)-benzimidazol-5-yl]methyl]-4-ethyl-aniline;
1-(4-ethoxyphenyl)-6-[2-(4-ethylphenyl)-ethyl]benzimidazole;
5-[2-(4-tert-butylphenyl)cyclopropyl]-1-(4-isopropoxyphenyl)-benzimidazol-
e; methyl
4-[(Z)-2-[1-(4-isopropoxyphenyl)-benzimidazol-5-yl]vinyl]benzoat-
e;
2-[4-[(Z)-2-[1-(4-isopropoxyphenyl)benzimidazol-5-yl]vinyl]phenyl]-prop-
an-2-ol;
5-[(Z)-2-[4-(1-fluoro-1-methyl-ethyl)phenyl]vinyl]-1-(4-isopropox-
y-phenyl)benzimidazole;
5-[(Z)-2-(4-isopropenylphenyl)-vinyl]-1-(4-isopropoxyphenyl)-benzimidazol-
e;
5-[4-[(Z)-2-[1-(4-isopropoxyphenyl)benzimidazol-5-yl]vinyl]phenyl]nonan-
-5-ol;
2-[4-[(Z)-2-[1-(5-isopropoxy-2-pyridyl)benzimidazol-5-yl]vinyl]phen-
yl]propan-2-ol;
1-(4-isopropoxyphenyl)-5-[(Z)-2-[4-(2,2,2-trifluoro-1,1-dimethyl-ethyl)ph-
enyl]vinyl]benzimidazole;
3-[4-[(Z)-2-[1-(4-isopropoxyphenyl)benzimidazol-5-yl]vinyl]phenyl]propana-
l; 4-[(Z)-2-[1-(4-isopropoxyphenyl)benzimidazol-5-yl]vinyl]benzoic
acid;
1,1,1-trifluoro-2-[4-[(Z)-2-[1-(4-isopropoxyphenyl)benzimidazol-5-yl]viny-
l]phenyl]propan-2-ol;
1,1,1,3,3,3-hexafluoro-2-[4-[(Z)-2-[1-(4-isopropoxyphenyl)benzimidazol-5--
yl]vinyl]phenyl]propan-2-ol;
1-[4-[(Z)-2-[1-(4-isopropoxyphenyl)benzimidazol-5-yl]vinyl]phenyl]cyclopr-
opanol;
4-[(Z)-2-[1-(4-isopropoxyphenyl)benzimidazol-5-yl]vinyl]benzonitri-
le;
2-[4-[(Z)-2-[1-(4-isopropoxyphenyl)benzimidazol-5-yl]vinyl]phenyl]buta-
n-2-ol;
1-[4-[(Z)-2-[1-(4-isopropoxyphenyl)benzimidazol-5-yl]vinyl]phenyl]-
ethanol;
1-[4-[(Z)-2-[1-(4-isopropoxyphenyl)benzimidazol-5-yl]vinyl]phenyl-
]cyclobutanol;
3-[4-[(Z)-2-[1-(4-isopropoxyphenyl)benzimidazol-5-yl]vinyl]phenyl]oxetan--
3-ol;
1-[4-[(Z)-2-[1-(4-isopropoxyphenyl)benzimidazol-5-yl]vinyl]phenyl]cy-
clopropanamine;
2-hydroxy-2-[4-[(Z)-2-[1-(4-isopropoxyphenyl)benzimidazol-5-yl]vinyl]phen-
yl]propanoic acid;
1-[4-[(Z)-2-[1-(4-isopropoxyphenyl)benzimidazol-5-yl]vinyl]phenyl]cyclope-
ntanol;
1-[4-[(Z)-2-[1-(4-isopropoxyphenyl)benzimidazol-5-yl]vinyl]phenyl]-
cyclohexanol;
3-[4-[(Z)-2-[1-(4-isopropoxyphenyl)benzimidazol-5-yl]vinyl]phenyl]azetidi-
n-3-ol;
4-[4-[(Z)-2-[1-(4-isopropoxyphenyl)benzimidazol-5-yl]vinyl]phenyl]-
tetrahydropyran-4-ol;
2-[4-[(Z)-2-[1-(4-isopropoxyphenyl)benzimidazol-5-yl]vinyl]phenyl]propan--
2-amine; and
2-[4-[(Z)-2-[1-(4-ethoxyphenyl)benzimidazol-5-yl]vinyl]phenyl]propan-2-ol
shown below in Table 1.
More preferably, compounds of Formula I are selected from the group
consisting of:
5-[(Z)-2-(4-tert-butylphenyl)vinyl]-1-(4-isopropoxyphenyl)-benzimidazole;
1-(4-ethoxyphenyl)-5-[(4-ethylphenyl)-methoxy]benzimidazole; and
2-[4-[(Z)-2-[1-(4-isopropoxyphenyl)benzimidazol-5-yl]vinyl]phenyl]-propan-
-2-ol.
TABLE-US-00001 TABLE 1 Compounds of the invention of Formula I
Molecular Cmpd Chemical Structure Formula Analytical Data Chemical
Name 1 ##STR00005## C.sub.25H.sub.24N.sub.2O 1H NMR in CDCl3:
.delta. 8.04 (s, 1H), 7.96 (d, 1H), 7.53 (dd, 1H), 7.48 (d, 2H),
7.38- 7.43 (m, 3H), 7.05-7.22 (m, 6H), 4.12 (q, 2H), 2.67 (q, 2H),
1.48 (t, 3H), 1.26 (t, 3H); 13C NMR in CDCl3: .delta. 158.7, 144.4,
143.7, 143.1, 135.0, 133.8, 132.7, 128.9, 128.2, 128.2, 127.6,
126.4, 125.6, 122.2, 118.4, 115.6, 110.4, 63.9, 28.6, 15.5, 14.8;
Mass Spec: 369.3 (M + H).sup.+ 1-(4-ethoxyphenyl)- 5-[(E)-2-(4-
ethylphenyl)vinyl] benzimidazole 2 ##STR00006##
C.sub.25H.sub.24N.sub.2O 1H NMR in CDCl3: .delta. 8.01 (s, 1H),
7.78 (bs, 1H), 7.36-7.41 (m, 2H), 7.25-7.31 (m, 2H), 7.21 (d, 2H),
7.01-7.07 (m, 4H), 6.70 (d, 1H), 6.58 (d, 1H), 4.10 (q, 2H), 2.60
(q, 2H), 1.47 (t, 3H), 1.21 (t, 3H): 13C NMR in CDCl3: .delta.
158.7, 144.0, 143.1, 142.8, 134.7, 133.3, 132.2, 129.8, 129.5,
129.0, 128.8, 127.7, 125.5, 124.9, 120.6, 115.6, 109.9, 63.9, 28.6,
15.4, 14.8; Mass Spec: 369.0 (M + H).sup.+ 1-(4-ethoxyphenyl)-
5-[(Z)-2- (4-ethylphenyl)vinyl] benzimidazole 3 ##STR00007##
C.sub.25H.sub.24N.sub.2O 1H NMR in CDCl3: .delta. 8.04 (s, 1H),
7.96 (s, 1H), 7.40-7.55 (m, 6H), 7.06-7.26 (m, 6H), 3.90 (s, 3H),
2.88-2.97 (m, 1H), 1.27 (d, 6H): 13C NMR in CDCl3: .delta. 159.4,
148.3, 144.4, 143.1, 135.2, 133.8, 132.7, 129.1, 128.2, 127.6,
126.7, 126.4, 125.6, 122.3, 118.4, 115.2, 110.4, 55.7, 33.9, 23.9;
Mass Spec: 369.3 (M + H).sup.+ 5-[(E)-2-(4- isopropylphenyl)
vinyl]-1-(4- methoxyphenyl) benzimidazole 4 ##STR00008##
C.sub.27H.sub.28N.sub.2O 1H NMR in CDCl3: .delta. 8.04 (s, 1H),
7.96 (d, 1H), 7.48-7.54 (m, 3H), 7.38-7.43 (m, 5H), 7.15-7.27 (m,
2H), 7.04-7.10 (m, 2H), 4.12 (q, 2H), 1.48 (t, 3H), 1.34 (s, 9H);
13C NMR in CDCl3: .delta. 158.7, 150.5, 144.4, 143.1, 134.8, 133.9,
132.7, 128.9, 128.4, 127.5, 126.1, 125.6, 125.6, 122.3, 118.4,
115.6, 110.4, 63.9, 34.6, 31.3, 14.8; Mass Spec: 397.2 (M +
H).sup.+ 5-[(E)-2-(4-tert- butylphenyl)vinyl]- 1-(4-ethoxyphenyl)-
benzimidazole 5 ##STR00009## C.sub.27H.sub.28N.sub.2O 1H NMR in
CDCl3: .delta. 8.01 (s, 1H), 7.81 (s, 1H), 7.37-7.41 (m, 2H),
7.24-7.32 (m, 2H), 7.23 (m, 4H), 7.02-7.07 (m, 2H), 6.71 (d, 1H),
6.56 (d, 1H), 4.10 (q, 2H), 1.47 (t, 3H), 1.28 (s, 9H); 13C NMR in
CDCl3: .delta. 158.7, 150.0, 144.0, 142.8, 134.3, 133.3, 132.3,
129.8, 129.4, 129.0, 128.6, 125.5, 125.1, 124.9, 120.6, 115.6,
110.0, 63.9, 34.5, 31.3, 14.8; Mass Spec: 397.2 (M + H).sup.+
5-[(Z)-2-(4-tert- butylphenyl) vinyl]-(4- ethoxyphenyl)
benzimidazole 6 ##STR00010## C.sub.28H.sub.30N.sub.2O 1H NMR in
CDCl3: .delta. 8.04 (s, 1H), 7.96 (s, 1H), 7.38-7.55 (m, 8H),
7.15-7.7.27 (m, 2H), 7.04-7.08 (m, 2H), 4.61-4.65 (m, 1H), 1.41 (d,
6H), 1.34 (s, 9H); Mass Spec: 411.0 (M + H).sup.+ 5-[(E)-2-(4-tert-
butylphenyl)vinyl]- 1-(4- isopropoxyphenyl)- benzimidazole 7
##STR00011## C.sub.28H.sub.30N.sub.2O 1H NMR in CDCl3: .delta. 8.01
(s, 1H), 7.81 (d, 1H), 7.36-7.40 (m, 2H), 7.18-7.33 (m, 6H),
7.01-7.05 (m, 2H), 6.71 (d, 1H), 6.56 (d, 1H), 4.59-4.63 (m, 1H),
1.39 (d, 6H), 1.29 (s, 9H); 13C NMR in CDCl3: .delta. 157.7, 150.0,
144.0, 142.9, 134.3, 133.3, 132.3, 129.8, 129.4, 128.8, 128.6,
125.6, 125.1, 124.9, 120.6, 116.8, 110.0, 70.4, 34.5, 31.3, 22.0;
Mass Spec: 411.0 (M + H).sup.+ 5-[(Z)-2-(4-tert-
butylphenyl)vinyl]- 1-(4- isopropoxyphenyl)- benzimidazole 8
##STR00012## C.sub.26H.sub.26N.sub.2O 1H NMR in CDCl3: .delta. 8.04
(s, 1H), 7.96 (d, 1H), 7.37-7.54 (m, 6H), 7.04-7.22 (m, 6H),
4.59-4.65 (m, 1H), 2.67 (q, 2H), 1.41 (d, 6H), 1.26 (t, 3H); Mass
Spec: 383.1 (M + H).sup.+ 5-[(E)-2-(4- ethylphenyl)vinyl]- 1-(4-
isopropoxyphenyl)- benzimidazole 9 ##STR00013##
C.sub.26H.sub.26N.sub.2O 1H NMR in CDCl3: .delta. 8.01 (s, 1H),
7.78 (d, 1H), 7.35-7.40 (m, 2H), 7.19-7.31 (m, 4H), 7.02-7.05 (m,
4H), 6.71 (d, 1H), 6.58 (d, 1H), 4.57-4.63 (m, 1H), 2.60 (q, 2H),
1.39 (d, 6H), 1.21 (t, 3H); 13C NMR in CDCl3: .delta. 157.7, 144.0,
143.1, 142.9, 134.7, 133.3, 132.2, 129.8, 129.5, 128.8, 127.7,
125.5, 124.9, 120.6, 116.8, 109.9, 70.4, 28.6, 22.0, 15.4; Mass
Spec: 383.1 (M + H).sup.+ 5-[(Z)-2-(4- ethylphenyl)vinyl]- 1-(4-
isopropoxyphenyl)- benzimidazole 10 ##STR00014##
C.sub.24H.sub.19F.sub.3N.sub.2O.sub.2 1H NMR in CDCl3: .delta. 8.06
(s, 1H), 7.98 (s, 1H), 7.51-7.58 (m, 3H), 7.39-7.45 (m, 3H),
7.21-7.28 (m, 3H), 7.05-7.14 (m, 3H), 4.13 (q, 2H), 1.49 (t, 3H);
Mass Spec: 425.1 (M + H).sup.+ 1-(4-ethoxyphenyl)- 5-[(E)-2-[4-
(trifluoromethoxy) phenyl] vinyl]benzimidazole 11 ##STR00015##
C.sub.24H.sub.19F.sub.3N.sub.2O.sub.2 1H NMR in CDCl3: .delta. 8.02
(s, 1H), 7.75 (d, 1H), 7.36-7.41 (m, 2H), 7.27-7.32 (m, 4H), 7.18
(dd, 1H), 7.03-7.08 (m, 3H), 6.80 (d, 1H), 6.56 (d, 1H), 4.10 (q,
2H), 1.47 (t, 3H); 13C NMR in CDCl3: .delta. 158.8, 148.0, 144.0,
143.1, 136.0, 133.5, 131.5, 131.4, 130.3, 128.8, 127.9, 125.6,
124.7, 120.7, 120.6, 115.6, 110.2, 63.9, 14.8; Mass Spec: 425.1 (M
+ H).sup.+ 1-(4-ethoxyphenyl)- 5-[(Z)-2-[4- (trifluoromethoxy)
phenyl]vinyl] benzimidazole 12 ##STR00016##
C.sub.24H.sub.19F.sub.3N.sub.2O 1H NMR in CDCl3: .delta. 8.07 (s,
1H), 8.00 (s, 1H), 7.59-7.66 (m, 4H), 7.55 (d, 1H), 7.33-7.46 (m,
4H), 7.06-7.18 (m, 3H), 4.13 (q, 2H), 1.49 (1, 3H); Mass Spec:
409.2 (M + H).sup.+ 1-(4-ethoxyphenyl)- 5-[(E)-2-[4-
(trifluoromethyl) phenyl]vinyl] benzimidazole 13 ##STR00017##
C.sub.24H.sub.19F.sub.3N.sub.2O 1H NMR in CDCl3: .delta. 8.03 (s,
1H), 7.74 (s, 1H), 7.26-7.47 (m, 7H), 7.16 (d, 1H), 7.03-7.08 (m,
2H), 6.87 (d, 1H), 6.61 (d, 1H), 4.11 (q, 2H), 1.47 (t, 3H); 13C
NMR in CDCl3: .delta. 158.8, 144.0, 143.1, 133.7, 132.6, 131.3,
129.2, 128.8, 128.0, 125.6, 125.2, 125.2, 125.1, 125.1, 124.7,
120.8, 115.6, 110.2, 63.9, 14.8; Mass Spec: 409.2 (M + H).sup.+
1-(4-ethoxyphenyl)- 5-[(Z)-2-[4- (trifluoromethyl) phenyl]vinyl]
benzimidazole 14 ##STR00018## C.sub.27H.sub.28N.sub.2O 1H NMR in
CDCl3: .delta. 8.07 (s, 1H), 7.97 (d, 1H), 7.46-7.55 (m, 4H),
7.38-7.42 (m, 2H), 7.10-7.22 (m, 6H), 2.67 (q, 2H), 1.43 (s, 9H),
1.26 (t, 3H); 13C NMR in CDCl3: .delta. 155.4, 144.5, 143.7, 143.0,
135.0, 133.6, 132.8, 131.4, 128.2, 128.2, 127.7, 126.4, 125.2,
124.7, 122.3, 118.4, 110.5, 79.4, 28.9, 28.6, 15.5: Mass Spec:
397.2 (M + H).sup.+ 1-(4-tert- butoxyphenyl)-5- [(E)-2-(4-
ethylphenyl)- vinyl] benzimidazole 15 ##STR00019##
C.sub.27H.sub.28N.sub.2O 1H NMR in CDCl3: .delta. 8.04 (s, 1H),
7.79 (d, 1H), 7.33-7.40 (m, 3H), 7.14-7.27 (m, 5H), 7.04 (d, 2H),
6.71 (d, 1H), 6.58 (d, 1H), 2.60 (q, 2H), 1.41 (s,9H), 1.21 (t,
3H); 13C NMR in CDCl3: .delta. 155.3, 144.1, 143.1, 142.7, 134.6,
133.0, 132.4, 131.4, 129.7, 129.6, 128.8, 127.7, 125.2, 125.0,
124.6, 120.7, 110.0, 79.4, 28.8, 28.6, 15.3; Mass Spec: 397.2 (M +
H).sup.+ 1-(4-tert- butoxyphenyl)- 5-[(Z)-2-(4- ethylphenyl)-
vinyl] benzimidazole 16 ##STR00020## C.sub.29H.sub.32N.sub.2O 1H
NMR in CDCl3: .delta. 8.07 (s, 1H), 7.97 (s, IH), 7.46-7.55 (m,
4H), 7.38-7.42 (m, 4H), 7.10-7.27 (m, 4H), 1.43 (s, 9H), 1.34 (s,
9H); 13C NMR in CDCl3: .delta. 155.4, 150.5, 144.5, 143.0, 134.8,
133.6, 132.8, 131.4, 128.3, 127.6, 126.1, 125.6, 125.2, 124.7,
122.3, 118.4, 110.5, 79.4, 34.6, 31.3, 28.9; Mass Spec: 425.1 (M +
H).sup.+ 1-(4-tert- butoxyphenyl)- 5-[(E)-2-(4-tert-
butylphenyl)vinyl] benzimidazole 17 ##STR00021##
C.sub.29H.sub.32N.sub.2O 1H NMR in CDCl3: .delta. 8.05 (s, 1H),
7.81 (d, 1H), 7.35-7.41 (m, 3H), 7.28 (dd, 1H), 7.23 (s, 4H),
7.14-7.19 (m, 2H), 6.71 (d, 1H), 6.56 (d, 1H), 1.42 (s, 9H), 1.29
(s, 9H); 13C NMR in CDCl3: .delta. 155.3, 150.0, 144.1, 142.7,
134.3, 133.0, 132.4, 131.4, 129.7, 129.4, 128.6, 125.2, 125.1,
125.0, 124.6, 120.6, 110.0, 79.4, 34.5, 31.3, 28.8; Mass Spec:
425.1 (M + H).sup.+ 1-(4-tert- butoxyphenyl)- 5-[(Z)-2-(4-tert-
butylphenyl)vinyl] benzimidazole 18 ##STR00022##
C.sub.24H.sub.23N.sub.3O .cndot. HCl 1H NMR in DMSO-d6: .delta.
9.61 (s, 1H), 8.40 (d, 1H), 8.21 (d, 1H), 8.02 (d, 1H), 7.96 (d,
1H), 7.83 (dd, 1H), 7.78 (dd, 1H), 7.57 (d, 2H), 7.38 (d, 2H), 7.25
(d, 2H), 4.23 (q, 2H), 2.63 (q, 2H), 1.41 (t, 3H), 1.20 (t, 3H);
13C NMR in DMSO-d6: .delta. 155.0, 144.0, 142.4, 141.9, 136.7,
135.1, 134.9, 130.6, 129.4, 128.6, 127.5, 127.0, 125.3, 124.3,
117.5, 115.2, 115.0, 64.8, 28.4, 16.0, 15.0; Mass Spec: 370.2 (M +
H - HCl).sup.+ 1-(5-ethoxy-2- pyridyl)-5- [(E)-2-(4-
ethylphenyl)vinyl] benzimidazole hydrochloride 19 ##STR00023##
C.sub.24H.sub.23N.sub.3O .cndot. HCl 1H NMR in DMSO-d6: .delta.
9.68 (s, 1H), 8.37 (d, 1H), 8.11 (d, 1H), 7.95 (d, 1H), 7.77 (dd,
1H), 7.71 (s, 1H), 7.41 (dd, 1H), 7.13 (q, 4H), 6.74 (ABq, 2H),
4.22 (q, 2H), 2.57 (q, 2H), 1.40 (t, 3H), 1.16 (t, 3H); 13C NMR in
DMSO-d6: .delta. 155.1, 143.5, 142.2, 141.7, 136.9, 136.7, 134.8,
134.3, 131.1, 130.2, 129.1, 129.0, 128.3, 126.9, 125.2, 117.7,
116.8, 114.8, 64.9, 28.3, 15.8, 14.9; Mass Spec: 370.2 (M + H -
HCl).sup.+ 1-(5-ethoxy-2- pyridyl)-5- [(Z)-2-(4- ethylphenyl)vinyl]
benzimidazole hydrochloride 20 ##STR00024##
C.sub.26H.sub.27N.sub.3O .cndot. HCl 1H NMR in DMSO-d6: .delta.
9.48 (s, 1H), 8.39 (d, 1H), 8.20 (d, 1H), 8.01 (d, 1H), 7.95 (d,
1H), 7.74-7.82 (m, 2H), 7.58 (d, 2H), 7.36-7.43 (m, 4H), 4.23 (q,
2H), 1.40 (t, 3H), 1.30 (s, 9H); 13C NMR in DMSO- d6: .delta.
154.8, 150.8, 142.6, 142.1, 136.7, 134.7, 130.9, 129.0, 127.7,
126.7, 126.0, 125.3, 117.3, 115.7, 114.8, 64.8, 34.8, 31.5, 15.0;
Mass Spec: 398.1 (M + H - HCl).sup.+ 5-[(E)-2-(4-tert-
butylphenyl)vinyl]- 1-(5-ethoxy-2- pyridyl) benzimidazole
hydrochloride 21 ##STR00025## C.sub.26H.sub.27N.sub.3O .cndot. HCl
1H NMR in DMSO-d6: .delta. 9.59 (s, 1H), 8.36 (d, 1H), 8.11 (d,
1H), 7.94 (d, 1H), 7.76 (dd, 1H), 7.72 (s, 1H), 7.42 (d, 1H), 7.28
(d, 2H), 7.18 (d, 2H), 6.73 (ABq, 2H), 4.22 (q, 2H), 1.39 (t, 3H),
1.25 (s, 9H); 13C NMR in DMSO-d6: .delta. 155.0, 150.4, 142.3,
141.9, 136.7, 134.6, 134.0, 130.8, 130.3, 129.3, 128.8, 126.7,
125.6, 125.3, 117.6, 117.1, 114.7, 64.8, 34.8, 31.5, 14.9: Mass
Spec: 398.1 (M + H - HCl).sup.+ 5-[(Z)-2-(4-tert-
butylphenyl)vinyl]- 1-(5-ethoxy-2- pyridyl) benzimidazole
hydrochloride 22 ##STR00026## C.sub.24H.sub.23N.sub.3O 1H NMR in
CDCl3: .delta. 8.35 (d, 1H), 8.21 (s, 1H), 8.03 (d, 1H), 7.56-7.61
(m, 2H), 7.16-7.18 (m, 2H), 7.03-7.09 (m, 4H), 6.72 (d, IH), 6.65
(d, 1H), 4.10 (q, 2H), 2.60 (q, 2H), 1.46 (t, 3H), 1.22 (t, 3H);
13C NMR in CDCl3: .delta. 158.6, 146.1, 143.7, 143.6, 135.5, 134.0,
131.6, 128.9, 128.7, 128.0, 127.9, 127.8, 126.2, 125.2, 115.5,
63.9, 28.6, 15.3, 14.8; Mass Spec: 370.2 (M + H).sup.+
3-(4-ethoxyphenyl)- 6-[(Z)-2-(4- ethylphenyl) vinyl]imidazo[4,5-
b]pyridine 23 ##STR00027## C.sub.24H.sub.23N.sub.3O 1H NMR in
CDCl3: .delta. 8.56 (d, 1H), 8.27 (d, 1H), 8.25 (s, 1H), 7.60-7.63
(m, 2H), 7.49 (d, 2H), 7.18-7.25 (m, 4H), 7.06-7.09 (m, 2H), 4.11
(q, 2H), 2.67 (q, 2H), 1.47 (t, 3H), 1.26 (t, 3H); 13C NMR in
CDCl3: .delta. 158.7, 144.6, 144.2, 144.0, 136.0, 134.5, 129.4,
129.4, 128.3, 127.8, 126.5, 125.2, 124.6, 124.4, 115.6, 63.9, 28.7,
15.5, 14.8; Mass Spec: 370.2 (M + H).sup.+ 3-(4-ethoxyphenyl)-
6-[(E)-2-(4- ethylphenyl)vinyl] imidazo[4,5- b]pyridine 24
##STR00028## C.sub.24H.sub.23N.sub.3O 1H NMR in CDCl3: .delta. 8.37
(d, 1H), 8.22 (s, 1H), 8.05 (d, 1H), 7.58-7.63 (m, 2H), 7.17-7.20
(m, 2H), 7.05-7.10 (m, 4H), 6.71 (d, 1H), 6.65 (d, 1H), 3.87 (s,
3H), 2.82- 2.86 (m, 1H), 1.22 (d, 6H); 13C NMR in CDCl3: .delta.
159.3, 148.2, 146.1, 145.9, 143.6, 135.4, 134.1, 131.6, 128.9,
128.7, 127.9, 126.6, 126.1, 125.3, 115.0, 55.6, 33.8, 23.9; Mass
Spec: 370.2 (M + H).sup.+ 6-[(Z)-2-(4- isopropylphenyl)
vinyl]-3-(4- methoxyphenyl) imidazo[4,5- b]pyridine 25 ##STR00029##
C.sub.24H.sub.23N.sub.3O 1H NMR in CDCl3: .delta. 8.56 (d, 1H),
8.27 (d, 1H), 8.26 (s, 1H), 7.60-7.65 (m, 2H), 7.47-7.51 (m, 2H),
7.24-7.27 (m, 2H), 7.19 (d, 2H), 7.07-7.13 (m, 2H), 3.89 (s, 3H),
2.88-2.97 (m, 1H), 1.28 (d, 6H); 13C NMR in CDCl3: .delta. 159.3,
148.9, 146.6, 144.6, 144.0, 136.0, 134.6, 129.4, 128.0, 126.8,
126.5, 125.2, 124.6, 124.4, 115.0, 55.6, 33.9, 23.9; Mass Spec:
370.2 (M + H).sup.+ 6-[(E)-2-(4- isopropylphenyl) vinyl]-3-(4-
methoxyphenyl) imidazo[4,5- b]pyridine 26 ##STR00030##
C.sub.24H.sub.21N.sub.3O Mass Spec: 368.1 (M + H).sup.+
3-(4-ethoxyphenyl)- 6-[2-(4- ethylphenyl)- ethynyl]imidazo
[4,5-b]pyridine 27 ##STR00031## C.sub.25H.sub.26N.sub.2O 1H NMR in
CDCl3: .delta. 8.04 (s, 1H), 7.66 (bs, 1H), 7.35-7.42 (m, 3H),
7.10-7.17 (m, 5H), 7.02-7.08 (m, 2H), 4.11 (q, 2H), 2.92- 3.09 (m,
4H), 2.63 (q, 2H), 1.47 (t, 3H), 1.23 (t, 3H); 13C NMR in CDCl3:
.delta. 158.7, 144.0, 142.6, 141.8, 139.0, 136.7, 132.6, 129.1,
129.0, 128.4, 128.1, 127.8, 125.6, 124.5, 119.6, 115.6, 110.0,
63.9, 38.2, 38.1, 28.5, 15.7, 14.8; Mass Spec: 371.1 (M + H).sup.+
1-(4- ethoxyphenyl)- 5-[2-(4- ethylphenyl)- ethyl] benzimidazole 28
##STR00032## C.sub.24H.sub.25N.sub.3O 1H NMR in CDCl3: .delta. 8.25
(d, 1H), 8.23 (s, 1H), 7.92 (d, 1H), 7.57-7.62 (m, 2H), 7.11 (s,
4H), 7.04-7.09 (m, 2H), 4.10 (q, 2H), 3.05-3.11 (m, 2H), 2.93-2.99
(m, 2H), 2.62 (q, 2H), 1.46 (t, 3H), 1.23 (t, 3H); 13C NMR in
CDCl3: .delta. 158.6, 145.7, 145.6, 143.4, 142.0, 138.1, 135.6,
132.5, 128.4, 127.9, 127.8, 125.2, 115.5, 63.9, 37.8, 35.1, 28.4,
15.6, 14.8; Mass Spec: 372.3 (M + H).sup.+ 3-(4-ethoxyphenyl)-
6-[2- (4-ethylphenyl)- ethyl]imidazo[4,5- b]pyridine 29
##STR00033## C.sub.24H.sub.24N.sub.2O.sub.2 1H NMR in CDCl3:
.delta. 7.99 (s, 1H), 7.32- 7.41 (m, 6H), 7.22 (d, 2H), 7.01-7.07
(m, 3H), 5.11 (s, 2H), 4.10 (q, 2H), 2.66 (q, 2H), 1.47 (t, 3H),
1.24 (t, 3H); 13C NMR in CDCl3: .delta. 158.6, 155.5, 144.6, 144.1,
142.6, 134.3, 129.1, 129.0, 128.1, 127.8, 125.4, 115.6, 114.4,
110.8, 103.8, 70.7, 63.9, 28.6, 15.6, 14.8; Mass Spec: 373.2 (M +
H).sup.+ 1-(4-ethoxyphenyl)- 5- [(4-ethylphenyl)- methoxy]
benzimidazole 30 ##STR00034## C.sub.24H.sub.24N.sub.2O.sub.2 1H NMR
in CDCl3: .delta. 7.98 (s, 1H), 7.37- 7.42 (m, 5H), 7.33 (d, 1H),
7.24-7.26 (m, 2H), 7.01-7.08 (m, 3H), 5.11 (s, 2H), 3.88 (s, 3H),
2.87-2.96 (m, 1H), 1.26 (d, 6H); 13C NMR in CDCl3: .delta. 159.2,
155.6, 148.7, 144.6, 142.6, 134.5, 129.3, 129.0, 127.8, 126.7,
125.5, 115.1, 114.4, 110.7, 103.8, 70.7, 55.6, 33.9, 24.0; Mass
Spec: 373.2 (M + H).sup.+ 5-[(4- isopropylphenyl) methoxy]-1-(4-
methoxyphenyl) benzimidazole
31 ##STR00035## C.sub.23H.sub.23N.sub.3O.sub.2 1H NMR in CDCl3:
.delta. 8.27 (d, 1H), 8.19 (s, 1H), 7.69 (d, 1H), 7.56-7.61 (m,
2H), 7.39 (d, 2H), 7.23 (d, 2H), 7.03-7.08 (m, 2H), 5.13 (s, 2H),
4.09 (m, 2H), 2.66 (q, 2H), 1.46 (t, 3H), 1.24 (t, 3H); 13C NMR in
CDCl3: .delta. 158.6, 152.6, 144.4, 143.5, 141.9, 136.3, 136.0,
133.5, 128.2, 128.0, 127.8, 125.1, 115.5, 112.4, 71.3, 63.9, 28.6,
15.6, 14.8; Mass Spec: 374.1 (M + H).sup.+ 3-(4-ethoxyphenyl)- 6-
[(4-ethylphenyl)- methoxy]imidazo [4,5-b]pyridine 32 ##STR00036##
C.sub.23H.sub.23N.sub.3O.sub.2 1H NMR in CDCl3: .delta. 8.27 (d,
1H), 8.20 (s, 1H), 7.70 (d, 1H), 7.57-7.63 (m, 2H), 7.40 (d, 2H),
7.26 (d, 2H), 7.05-7.10 (m, 2H), 5.13 (s, 2H), 3.87 (s, 3H),
2.88-2.97 (m, 1H), 1.26 (d, 6H); 13C NMR in CDCl3: .delta. 159.2,
152.7, 149.1, 143.5, 136.3, 136.0, 133.7, 128.1, 127.8, 126.8,
125.1, 115.0, 112.4, 71.3, 55.6, 33.9, 24.0; Mass Spec: 374.1 (M +
H).sup.+ 6-[(4-isopropyl- phenyl)methoxy]-3- (4- methoxyphenyl)
imidazo[4,5- b]pyridine 33 ##STR00037## C.sub.24H.sub.24N.sub.2OS
1H NMR in CDCl3: .delta. 8.02 (s, 1H), 7.88 (bs, 1H), 7.35-7.39 (m,
2H), 7.27-7.32 (m, 2H), 7.20 (d, 2H), 7.04-7.11 (m, 4H), 4.07- 4.14
(m, 4H), 2.61 (q, 2H), 1.47 (t, 3H), 1.21 (t, 3H); 13C NMR in
CDCl3: .delta. 158.8, 144.4, 143.1, 134.9, 133.4, 129.7, 128.8,
128.7, 127.9, 127.3, 125.6, 123.3, 1 15.6, 110.6, 63.9, 40.6, 28.5,
15.5, 14.8; Mass Spec: 389.1 (M + H).sup.+ 1-(4-ethoxyphenyl)- 5-
[(4-ethylphenyl)- methylsulfanyl] benzimidazole 34 ##STR00038##
C.sub.24H.sub.25N.sub.3O 1H NMR in CDCl3: .delta. 8.03 (s, 1H),
7.85 (s, 1H), 7.32-7.42 (m, 4H), 6.98-7.07 (m, 4H), 6.60-6.64 (m,
2H), 4.45 (s, 2H), 4.11 (q, 2H), 3.99 (bs, 1H), 2.53 (q, 2H), 1.47
(t, 3H), 1.18 (t, 3H); Mass Spec: 372.0 (M + H).sup.+ N-[[1-(4-
ethoxyphenyl) benzimidazol-5-yl] methyl]-4-ethyl- aniline 35
##STR00039## C.sub.25H.sub.26N.sub.2O 1H NMR in CDCl3: .delta. 7.99
(s, 1H), 7.77 (d, 1H), 7.31-7.36 (m, 2H), 7.16-7.20 (m, 2H),
7.02-7.13 (m, 6H), 4.11 (q, 2H), 2.99- 3.05 (m, 2H), 2.88-2.94 (m,
2H), 2.63 (q, 2H), 1.48 (t, 3H), 1.23 (t, 3H); 13C NMR in CDCl3:
.delta. 158.6, 142.3, 141.8, 138.9, 137.7, 129.1, 128.5, 127.8,
125.7, 123.6, 120.1, 115.6, 109.8, 63.9, 38.4, 38.1, 28.4, 15.7,
14.8; Mass Spec: 371.1 (M + H).sup.+ 1-(4-ethoxyphenyl)- 6-[2-
(4-ethylphenyl)- ethyl] benzimidazole 36 ##STR00040##
C.sub.29H.sub.32N.sub.2O 1H NMR in CDCl3: .delta. 8.01 (s, 1H),
7.60 (s, 1H), 7.31-7.40 (m, 5H), 7.08-7.16 (m, 3H), 7.01-7.06 (m,
2H), 4.57-4.63 (m, 1H), 2.29-2.35 (m, 1H), 2.16-2.22 (ra, 1H),
1.43-1.53 (m, 2H), 1.40 (d, 6H), 1.32 (s, 9H); 13C NMR in CDCl3:
.delta. 157.6, 148.6, 144.3, 142.7, 139.7, 137.4, 132.7, 129.0,
125.5, 125.5, 125.3, 122.6, 116.8, 110.1, 70.4, 34.4, 31.4, 28.0,
27.7, 22.0, 18.2; Mass Spec: 425.4 (M + H).sup.+ 5-[2-(4-tert-
butylphenyl) cyclopropyl]- 1-(4- isopropoxyphenyl)- benzimidazole
37 ##STR00041## C.sub.26H.sub.24N.sub.2O.sub.3 1H NMR in CDCl3:
.delta. 8.02 (s. 1H), 7.87 (d, 2H), 7.73 (s, 1H), 7.27-7.40 (m,
5H), 7.16 (dd, 1H), 7.03 (d, 2H), 6.87 (d, 1H), 6.63 (d, 1H),
4.57-4.65 (m, 1H), 3.88 (s, 3H), 1.39 (d, 6H); 13C NMR in CDCl3:
.delta. 166.9, 157.7, 144.0, 143.1, 142.4, 133.6, 132.6, 131.4,
129.6, 128.9, 128.7, 128.5, 128.4, 125.6, 124.8, 120.9, 116.9,
110.1, 70.4, 52.0, 22.0; Mass Spec: 413.1 (M + H).sup.+ methyl
4-[(Z)- 2-[1-(4- isopropoxyphenyl)- benzimidazol-5-
yl]vinyl]benzoate 38 ##STR00042## C.sub.27H.sub.28N.sub.2O.sub.2 1H
NMR in CDCl3: .delta. 8.00 (s, 1H), 7.78 (s, 1H), 7.38 (d, 2H),
7.22-7.35 (m, 6H), 7.03 (d, 2H), 6.74 (d, 1H), 6.58 (d, 1H),
4.57-4.65 (m, 1H), 1.56 (s, 6H), 1.39 (d, 6H); 13C NMR in CDCl3:
.delta. 157.7, 147.9, 144.0, 142.9, 135.8, 133.4, 132.1, 130.4,
129.1, 128.8, 125.6, 124.9, 124.3, 120.6, 116.8, 110.0, 72.4, 70.4,
31.6, 22.0; Mass Spec: 413.1 (M + H).sup.+ 2-[4-[(Z)-2-[1-(4-
isopropoxyphenyl) benzimidazol-5- yl]vinyl]phenyl]- propan-2-ol 39
##STR00043## C.sub.27H.sub.27FN.sub.2O 1H NMR in CDCl3: .delta.
8.04 (s, 1H), 7.78 (s, 1H), 7.38 (d, 2H), 7.20-7.32 (m, 6H), 7.037
(d, 2H), 6.76 (d, 1H), 6.58 (d, 1H), 4.57-4.63 (m, 1H), 1.70 (s,
3H), 1.62 (s, 3H), 1.39 (d, 6H); 13C NMR in CDCl3: .delta. 157.7,
142.9, 132.1, 130.6, 129.0, 128.8, 128.7, 125.6, 124.9, 123.8,
123.7, 120.5, 116.8, 110.1, 70.4, 29.3, 29.0, 22.0; Mass Spec:
395.1 (M - HF).sup.+ 5-[(Z)-2-[4-(1- fluoro-1-methyl- ethyl)phenyl]
vinyl]-1-(4- isopropoxy- phenyl) benzimidazole 40 ##STR00044##
C.sub.27H.sub.26N.sub.2O 1H NMR in CDCl3: .delta. 8.06 (s, 1H),
7.79 (s, 1H), 7.23-7.40 (m, 8H), 7.03 (d, 2H), 6.75 (d, 1H), 6.59
(d, 1H), 5.36 (s, 1H), 5.05 (s, 1H), 4.57-4.65 (m, 1H), 2.12 (s,
3H), 1.39 (d, 6H); 13C NMR in CDCl3: .delta. 157.8, 142.8, 142.8,
139.7, 136.5, 132.3, 130.4, 129.3, 128.8, 128.6, 126.3, 125.6,
125.3, 125.0, 120.5, 116.9, 112.2, 110.1, 70.4, 22.0, 21.7; Mass
Spec: 395.1 (M + H).sup.+ 5-[(Z)-2-(4- isopropenylphenyl)-
vinyl]-1-(4- isopropoxyphenyl)- benzimidazole 41 ##STR00045##
C.sub.33H.sub.40N.sub.2O.sub.2 1H NMR in CDCl3: .delta. 9.34 (s,
1H), 7.99 (s, 1H), 7.51 (d, 2H), 7.40 (dd, 1H), 7.32 (d, 1H), 7.24
(d, 2H), 7.08-7.14 (m, 4H), 6.77 (d, 1H), 6.69 (d, 1H), 4.60-4.66
(m, 1H), 1.71-1.78 (m, 4H), 1.40 (d, 6H), 1.18- 1.28 (m, 6H),
1.03-1.09 (m, 2H), 0.79-0.84 (m, 6H); 13C NMR in CDCl3: .delta.
159.7, 146.5, 138.9, 137.4, 134.3, 132.5, 131.8, 130.5, 128.5,
128.3, 128.0, 126.2, 125.6, 125.3. 117.2. 116.5, 111.8, 70.7, 42.3,
25.7, 23.1, 21.9, 14.0; Mass Spec: 497.4 (M + H).sup.+
5-[4-[(Z)-2-[1-(4- isopropoxyphenyl) benzimidazol-5-
yl]vinyl]phenyl] nonan-5-ol 42 ##STR00046##
C.sub.26H.sub.27N.sub.3O.sub.2 1H NMR in CDCl3: .delta. 8.40 (s,
1H), 8.23- 8.25 (m, 1H), 7.76-7.78 (m, 2H), 7.45 (d, 1H), 7.39 (dd,
1H), 7.24-7.34 (m, 5H), 6.74 (d, 1H), 6.59 (d, 1H), 4.61-4.65 (m,
1H), 1.56 (s, 6H), 1.41 (d, 6H); 13C NMR in CDCl3: .delta. 153.0,
147.9, 144.5, 142.7, 141.7, 137.9, 135.7, 132.5, 131.5, 130.3,
129.3, 128.8, 125.6, 125.3, 124.3, 120.7, 115.4, 111.7, 72.4, 71.3,
31.6, 21.9; Mass Spec: 414.3 (M + H).sup.+ 2-[4-[(Z)-2-[1-(5-
isopropoxy-2- pyridyl) benzimidazol-5- yl]vinyl]phenyl] propan-2-ol
43 ##STR00047## C.sub.28H.sub.27F.sub.3N.sub.2O 1H NMR in CDCl3:
.delta. 8.02 (s, 1H), 7.79 (s, 1H), 7.22-7.41 (m, 8H), 7.04 (dd,
2H), 6.77 (d, 1H), 6.57 (d, 1H), 4.59-4.63 (m, 1H), 1.54 (s, 6H),
1.40 (d, 6H);); 13C NMR in CDCl3: .delta. 157.7, 144.0, 143.0,
138.6, 136.6, 133.4, 131.9, 130.9, 130.2, 128.7, 128.7, 127.2,
126.5, 125.6, 124.8, 120.6, 116.9, 110.1, 70.4, 43.8, 43.5, 22.6,
22.5, 22.0; Mass Spec: 465.3 (M + H).sup.+ 1-(4-iso-
propoxyphenyl)- 5-[(Z)-2-[4-(2,2,2- trifluoro-1,1- dimethyl-ethyl)
phenyl]vinyl] benzimidazole 44 ##STR00048##
C.sub.27H.sub.26N.sub.2O.sub.2 Mass Spec: 411.3 (M + H).sup.+
3-[4-[(Z)-2-[1-(4- isopropoxyphenyl) benzimidazol-5- yl]vinyl]
phenyl]propanal 45 ##STR00049## C.sub.25H.sub.22N.sub.2O.sub.3 1H
NMR in CDCl3: .delta. 8.13 (s, 1H), 7.95 (d, 2H), 7.88 (s, 1H),
7.32-7.40 (m, 5H), 7.20 (dd, 1H), 7.01-7.07 (m, 2H), 6.83 (d, 1H),
6.65 (d, 1H), 4.57-4.65 (m, 1H), 1.39 (d, 6H);); 13C NMR in CDCl3:
.delta. 169.6, 157.9, 143.0, 142.4, 132.1, 131.6, 130.1, 128.8,
128.8, 128.7, 128.4, 125.7, 125.5, 120.3, 116.9, 110.4, 70.4, 27.0,
22.0; Mass Spec: 399.3 (M + H).sup.+ 4-[(Z)-2-[1-(4-
isopropoxyphenyl) benzimidazol-5- yl]vinyl] benzoic acid 46
##STR00050## C.sub.27H.sub.25F.sub.3N.sub.2O.sub.2 1H NMR in CDCl3:
.delta. 8.01 (s, 1H), 7.75 (s, 1H), 7.20-7.43 (m, 8H), 7.02-7.06
(m, 2H), 6.78 (d, 1H), 6.59 (d, 1H), 4.57-4.65 (m, 1H), 2.88 (s,
1H), 1.75 (s, 3H), 1.39 (d, 6H); 13C NMR in CDCl3: .delta. 174.2,
157.7, 143.8, 143.0, 137.7, 137.2, 131.8, 131.2, 128.8, 128.7,
126.0, 125.6, 124.9, 120.6, 116.9, 110.1, 70.4, 23.8, 22.0; Mass
Spec: 467.1 (M + H).sup.+ 1,1,1-trifluoro-2- [4-[(Z)- 2-[1-(4-
isopropoxyphenyl) benzimidazol-5- yl]vinyl]phenyl] propan-2-ol 47
##STR00051## C.sub.27H.sub.22F.sub.6N.sub.2O.sub.2 1H NMR in CDCl3:
.delta. 7.99 (s, 1H), 7.62 (s, 2H), 7.59 (s, 1H), 7.29-7.39 (m,
5H), 7.20 (dd, 1H), 7.02-7.06 (m, 2H), 6.87 (bs, 1H), 6.77 (d, 1H),
6.58 (d, 1H), 4.57-4.65 (m, 1H), 1.39 (d, 6H); Mass Spec: 521.1 (M
+ H).sup.+ 1,1,1,3,3,3- hexafluoro- 2-[4-[(Z)-2-[1-(4-
isopropoxyphenyl) benzimidazol-5- yl]vinyl]phenyl] propan-2-ol 48
##STR00052## C.sub.27H.sub.26N.sub.2O.sub.2 1H NMR in CDCl3:
.delta. 8.02 (s, 1H), 7.76 (s, 1H), 7.22-7.40 (m, 6H), 7.14-7.16
(m, 2H), 7.03-7.06 (m, 2H), 6.75 (d, 1H), 6.60 (d, 1H), 4.58-4.64
(m, 1H), 1.40 (d, 6H), 1.23-1.27 (m, 2H), 1.01-1.05 (m, 2H); Mass
Spec: 411.3 (M + H).sup.+ 1-[4-[(Z)-2-[1-(4- isopropoxyphenyl)
benzimidazol-5- yl]vinyl]phenyl] cyclopropanol 49 ##STR00053##
C.sub.25H.sub.21N.sub.3O 1H NMR in CDCl3: .delta. 8.03 (s, 1H),
7.71 (s, 1H), 7.48 (dd, 2H), 7.26-7.40 (m, 5H), 7.12 (dd, 1H),
7.02-7.06 (m, 2H), 6.91 (d, 1H), 6.58 (d, 1H), 4.57-4.65 (m, 1H),
1.39 (d, 6H); 13C NMR in CDCl3: .delta. 157.8, 144.1, 143.3, 142.4,
133.8, 133.7, 132.1, 130.9, 129.6, 128.6, 127.7, 125.6, 124.7,
120.8, 119.0, 116.9, 110.4, 110.3, 70.5, 22.0; Mass Spec: 380.1 (M
+ H).sup.+ 4-[(Z)-2-[1-(4- isopropoxyphenyl) benzimidazol-5-
yl]vinyl] benzonitrile 50 ##STR00054##
C.sub.28H.sub.30N.sub.2O.sub.2 1H NMR in CDCl3: .delta. 8.00 (s,
1H), 7.77 (s, 1H), 7.36-7.39 (m, 2H), 7.21-7.31 (m, 6H), 7.02-7.05
(m, 2H), 6.73 (d, 1H), 6.58 (d, 1H);); 13C NMR in CDCl3: .delta.
157.7, 146.6, 143.9, 142.9, 135.6, 133.4, 132.1, 130.3, 129.2,
128.8, 128.7, 125.6, 124.9, 124.8, 120.6, 116.9, 110.0, 74.8, 70.4,
36.6, 29.4, 22.0, 8.4; Mass Spec: 427.2 (M + H).sup.+
2-[4-[(Z)-2-[1-(4- isopropoxyphenyl) benzimidazol-5-
yl]vinyl]phenyl] butan-2-ol 51 ##STR00055##
C.sub.26H.sub.26N.sub.2O.sub.2 1H NMR in CDCl3: .delta. 7.99 (s,
1H), 7.74 (s, 1H), 7.34-7.39 (m, 2H), 7.20-7.31 (m, 6H), 7.00-7.06
(m, 2H), 7.74 (d, 1H), 6.59 (d, 1H);); 13C NMR in CDCl3: .delta.
157.7, 144.6, 143.9, 142.9, 136.6, 133.4, 132.0, 130.5, 129.2,
129.0, 128.7, 125.6, 125.4, 124.9, 120.6, 116.9, 110.0, 70.4, 70.2,
24.9, 22.0; Mass Spec: 399.3 (M + H).sup.+ 1-[4-[(Z)-2-[1-(4-
isopropoxyphenyl) benzimidazol-5- yl]vinyl] phenyl]ethanol 52
##STR00056## C.sub.28H.sub.28N.sub.2O.sub.2 1H NMR in CDCl3:
.delta. 7.99 (s, 1H), 7.76 (s, 1H), 7.21-7.40 (m, 8H), 7.00-7.05
(m, 2H), 6.75 (d, 1H), 6.59 (d, 1H), 4.57-4.65 (m, 1H), 2.48-2.58
(m, 2H), 2.29-2.39 (m, 2H), 2.19 (s, 1H), 1.95-2.07 (m, 1H), 1.63-
1.75 (m, 1H), 1.39 (d, 6H); 13C NMR in CDCl3: .delta. 157.7, 145.1,
143.9, 142.9, 136.4, 133.4, 132.0, 130.6, 129.1, 129.0, 128.8,
125.6, 124.9, 120.7, 116.9, 110.1, 70.4, 36.8, 22.0, 13.0; Mass
Spec: 425.1 (M + H).sup.+ 1-[4-[(Z)-2-[1-(4- isopropoxyphenyl)
benzimidazol-5- yl]vinyl]phenyl] cyclobutanol 53 ##STR00057##
C.sub.27H.sub.26N.sub.2O.sub.3 1H NMR in CDCl3: .delta. 7.95 (s,
1H), 7.69 (s, 1H), 7.43-7.46 (m, 2H), 7.28-7.38 (m, 5H), 7.21 (dd,
1H), 7.00-7.05 (m, 2H), 6.75 (d, 1H), 6.61 (d, 1H), 4.81-4.87 (m,
4H), 4.56-4.64 (m, 1H), 1.39 (d, 6H); 13C NMR in CDCl3: .delta.
157.9, 143.7, 143.1, 141.8, 137.1, 133.6, 132.1, 131.1, 129.3,
129.2, 128.8, 125.8, 125.3, 124.8, 120.6, 117.1, 110.4, 85.9, 75.6,
70.7, 22.4; Mass Spec: 427.2 (M + H).sup.+ 3-[4-[(Z)-2-[1-(4-
isopropoxyphenyl) benzimidazol-5- yl]vinyl]phenyl] oxetan-3-ol 54
##STR00058## C.sub.27H.sub.27N.sub.3O 1H NMR in CDCl3: .delta. 8.00
(s, 1H), 7.77 (s, 1H), 7.34-7.39 (m, 2H), 7.21-7.31 (m, 4H),
7.10-7.12 (m, 2H), 7.00-7.06 (m, 2H), 6.72 (d, 1H), 6.56 (d, 1H),
4.56-4.64 (m, 1H), 1.39 (d, 6H), 1.01-1.06 (m, 2H), 0.93-0.98 (m,
2H);); 13C NMR in CDCl3: .delta. 157.7, 145.7, 143.9, 142.9, 135.0,
133.4, 132.1, 130.2, 129.1, 128.9, 128.8, 125.5, 125.1, 124.9,
120.6, 116.8, 110.0, 72.5, 70.4, 61.6, 36.5, 22.0, 18.0; Mass Spec:
410.1 (M + H).sup.+ 1-[4-[(Z)-2-[1-(4- isopropoxyphenyl)
benzimidazol-5- yl]vinyl]phenyl] cyclopropanamine 55 ##STR00059##
C.sub.27H.sub.26N.sub.2O.sub.4 1H NMR in CDCl3: .delta. 8.03 (s,
1H), 7.54 (s, 1H), 7.39 (d, 2H), 7.08-7.30 (m, 6H), 6.98 (d, 2H),
6.63 (d, 1H), 6.52 (d, 1H), 4.54-4.62 (m, 1H), 1.69 (s, 3H), 1.37
(d, 6H); Mass Spec: 443.1 (M + H).sup.+ 2-hydroxy-2-[4-[(Z)-
2-[1-(4- isopropoxyphenyl) benzimidazol-5- yl]vinyl]phenyl]
propanoic acid 56 ##STR00060## C.sub.29H.sub.30N.sub.2O.sub.2 1H
NMR in CDCl3: .delta. 8.00 (s, 1H), 7.77 (s, 1H), 7.22-7.40 (m,
8H), 7.00-7.06 (m, 2H), 6.74 (d, 1H), 6.58 (d, 1H), 4.57-4.65 (m,
1H), 1.97 (s, 6H), 1.81-1.95 (m, 2H), 1.39 (d, 6H): 13C NMR in
CDCl3: .delta. 157.7, 145.9, 143.9, 142.9, 135.9, 133.4, 132.1,
130.4, 129.2, 128.8, 125.6, 125.0, 124.9, 120.6, 116.9, 110.1,
83.4, 70.4, 41.7, 23.8, 22.0; Mass Spec: 439.2 (M + H).sup.+
1-[4-[(Z)-2-[1-(4- isopropoxyphenyl) benzimidazol-5-
yl]vinyl]phenyl] cyclopentanol 57 ##STR00061##
C.sub.30H.sub.32N.sub.2O.sub.2 1H NMR in CDCl3: .delta. 8.00 (s,
1H), 7.77 (s, 1H), 7.22-7.39 (m, 8H), 7.01-7.05 (m, 2H), 6.73 (d,
1H), 6.58 (d, 1H), 4.59-4.63 (m, 1H), 1.59-1.81 (m, 10H), 1.39 (d,
6H); 13C NMR in CDCl3: .delta. 157.7, 148.2, 143.9, 142.9, 135.8,
133.4, 132.1, 130.3, 129.2, 128.8, 125.6, 124.9, 124.5, 120.6,
116.9, 110.0, 73.0, 70.4, 38.7, 25.5, 22.2, 22.0; Mass Spec: 453.3
(M + H).sup.+ 1-[4-[(Z)-2-[1-(4- isopropoxyphenyl) benzimidazol-5-
yl]vinyl]phenyl] cyclohexanol 58 ##STR00062##
C.sub.27H.sub.27N.sub.3O.sub.2 1H NMR in CDCl3: .delta. 7.94 (s,
1H), 7.51 (s, 1H), 7.29-7.35 (m, 5H), 7.19-7.25 (m, 3H), 7.01 (d,
2H), 6.71 (d, 1H), 6.54 (d, 1H), 4.55-4.63 (m, 1H), 4.31 (d, 2H),
4.11 (d, 2H), 1.38 (d, 6H); Mass Spec: 426.3 (M + H).sup.+
3-[4-[(Z)-2-[1-(4- isopropoxyphenyl) benzimidazol-5-
yl]vinyl]phenyl] azetidin-3-ol 59 ##STR00063##
C.sub.29H.sub.30N.sub.2O.sub.3 1H NMR in CDCl3: .delta. 7.99 (s,
1H), 7.75 (s, 1H), 7.21-7.39 (m, 8H), 7.01-7.06 (m, 2H), 6.75 (d,
1H), 6.58 (d, 1H), 4.57-4.65 (m, 1H), 3.81-3.96 (m, 4H), 2.04-2.19
(m, 2H), 1.70 (s, 2H), 1.39 (d, 6H); 13C NMR in CDCl3: .delta.
157.7, 146.9, 143.9, 142.9, 136.4, 133.4, 132.0, 130.7,129.0,
129.0, 128.7, 125.6, 125.0, 124.5, 120.5, 116.9, 110.1, 70.5, 70.5,
63.9, 38.7, 22.0; Mass Spec: 455.4 (M + H).sup.+ 4-[4-[(Z)-2-[1-(4-
isopropoxyphenyl) benzimidazol-5- yl]vinyl]phenyl) tetrahydropyran-
4-ol 60 ##STR00064## C.sub.27H.sub.29N.sub.3O 1H NMR in CDCl3:
.delta. 7.97 (s, 1H), 7.77 (s, 1H), 7.22-7.40 (m, 8H), 7.00-7.06
(m, 2H), 6.73 (d, 1H), 6.56 (d, 1H), 4.57-4.65 (m, 1H), 1.50 (s,
6H), 1.39 (d, 6H);); 13C NMR in CDCl3: .delta. 157.7, 143.9, 142.9,
135.5, 133.4, 132.1, 130.3, 129.1, 128.8, 125.6, 125.0, 124.7,
120.6, 116.9, 110.1, 70.4, 52.8, 32.0, 22.0; Mass Spec: 434.4 (M +
Na).sup.+ 2-[4-[(Z)-2-[1-(4- isopropoxyphenyl) benzimidazol-5-
yl]vinyl] phenyl]propan- 2-amine
61 ##STR00065## C.sub.26H.sub.26N.sub.2O.sub.2 1HNMR in CDCl3:
.delta. 8.01 (s, 1H), 7.78 (s, 1H), 7.23-7.42 (m, 8H), 7.03-7.08
(m, 2H), 6.75 (d, 1H), 6.59 (d, 1H), 4.11 (q, 2H), 1.57 (s, 6H),
1.48 (t, 3H); 13C NMR in CDCl3: .delta. 158.7, 147.9, 143.9, 142.9,
135.8, 133.4, 132.1, 130.4, 129.1, 128.9, 128.8, 125.6, 124.9,
124.3, 120.6, 115.6, 110.0, 72.4, 63.9, 31.6, 14.8; Mass Spec:
399.3 (M + H).sup.+ 2-[4-[(Z)-2-[1-(4- ethoxyphenyl)
benzimidazol-5- yl]vinyl] phenyl]propan- 2-ol
The compounds of the invention include compounds which are of the
following general Formula II or a pharmaceutically acceptable salt
thereof:
##STR00066##
wherein, E is independently N, N.sup.+--O.sup.-, or C--R; G, L, M,
and Q are independently N or C--R; and J and K are independently N
or C with the proviso that when n=0, E and J cannot both be N;
R is selected from the group consisting of hydrogen, substituted or
unsubstituted alkyl, haloalkyl, alkenyl, alkynyl, cycloalkyl,
heterocycloalkyl, arylalkyl, aryl, heteroaryl, hydroxy, alkyloxy,
aryloxy, heteroaryloxy, acyloxy, arylacyloxy, heteroarylacyloxy,
alkylsulfonyloxy, arylsulfonyloxy, thio, alkylthio, arylthio,
amino, alkylamino, dialkylamino, cycloalkylamino,
heterocycloalkylamino, arylamino, heteroarylamino, acylamino,
arylacylamino, heteroarylacylamino, alkylsulfonylamino,
arylsulfonylamino, acyl, arylacyl, heteroarylacyl, alkylsulfinyl,
arylsulfinyl, heteroarylsulfinyl, hydroxysulfonyl, alkylsulfonyl,
arylsulfonyl, heteroarylsulfonyl, aminosulfonyl, substituted
aminosulfonyl, carboxy, alkoxycarbonyl, cycloalkyloxycarbonyl,
aryloxycarbonyl, carbamoyl, substituted carbamoyl, halogen, cyano,
isocyano and nitro;
R' is as follows: (a) R' is independently selected from the group
consisting of: hydrogen, alkyl, alkenyl, alkynyl, cycloalkyl,
heterocycloalkyl, arylalkyl, aryl, heteroaryl, acyl, arylacyl,
heteroarylacyl, alkylsulfinyl, arylsulfinyl, heteroarylsulfinyl,
hydroxysulfonyl, alkylsulfonyl, arylsulfonyl, heteroarylsulfonyl,
aminosulfonyl, substituted aminosulfonyl, alkoxycarbonyl,
cycloalkyloxycarbonyl, aryloxycarbonyl, carbamoyl and substituted
carbamoyl; (b) R' together with the nitrogen atom it is attached
to, the carbon atom R.sup.1 and R.sup.2 are attached to, R.sup.1 or
R.sup.2, form a substituted or unsubstituted ring, which optionally
includes one or more heteroatoms in the ring; (c) R' together with
the nitrogen atom it is attached to, the carbon atom R.sup.1 and
R.sup.2 are attached to, some carbons of Ar.sup.2, form a
substituted or unsubstituted ring, which optionally includes one or
more heteroatoms in the ring; or (d) R' together with the nitrogen
atom it is attached to, some carbons of the aromatic ring next to
this nitrogen, form a substituted or unsubstituted ring, which
optionally includes one or more heteroatoms in the ring;
R.sup.1 and R.sup.2 are as follows: (a) R.sup.1 and R.sup.2 are
independently selected from the group consisting of hydrogen,
alkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, arylalkyl,
aryl, heteroaryl, acyl, arylacyl, heteroarylacyl, alkylsulfinyl,
arylsulfinyl, heteroarylsulfinyl, hydroxysulfonyl, alkylsulfonyl,
arylsulfonyl, heteroarylsulfonyl, aminosulfonyl, substituted
aminosulfonyl, alkoxycarbonyl, cycloalkyloxycarbonyl,
aryloxycarbonyl, carbamoyl and substituted carbamoyl; (b) R.sup.1
and R.sup.2 together with the carbon atom they are attached to form
a substituted or unsubstituted ring, which optionally include one
or more heteroatoms in the ring; (c) R.sup.1 or R.sup.2 together
with the carbon atom it is attached to, the nitrogen next to this
carbon, and some carbons of the aromatic ring next to this
nitrogen, form a substituted or unsubstituted ring, which
optionally include one or more heteroatoms in the ring; or (d)
R.sup.1 or R.sup.2 together with the carbon atom it is attached to,
some carbons of Ar.sup.2, form a substituted or unsubstituted ring,
which optionally includes one or more heteroatoms in the ring;
n is an integer from 0-4; and
Ar.sup.1 and Ar.sup.2 are independently (un)substituted aryl or
heteroaryl.
Preferably for compounds of Formula II, each of E and K is N; each
of G, L, M and Q is C--R and R is hydrogen; and J is C.
Preferably, the compound of Formula II of the present invention is
selected from the group consisting of
3-[(4-ethoxyphenyl)methyl]-N-[(4-ethylphenyl)-methyl]imidazo-[4,5-b]pyrid-
in-6-amine;
1-(4-ethoxyphenyl)-N-[(4-ethylphenyl)-methyl]indol-5-amine;
3-(4-ethoxyphenyl)-N-[(4-ethylphenyl)-methyl]-1H-indol-6-amine;
3-(4-ethoxyphenyl)-N-[(4-ethylphenyl)-methyl]imidazo[1,2-a]pyridin-7-amin-
e;
1-(4-ethoxyphenyl)-N-[(4-ethylphenyl)-methyl]pyrrolo[2,3-b]pyridin-5-am-
ine; and
1-(4-ethoxyphenyl)-N-[(4-ethylphenyl)-methyl]-3-oxido-benzimidazo-
l-3-ium-5-amine shown below in Table 2.
TABLE-US-00002 TABLE 2 Compounds of the invention of Formula II
Molecular Cmpd Chemical Structure Formula Analytical Data Chemical
Name 62 ##STR00067## C.sub.24H.sub.26N.sub.4O 1H NMR in CDCl3:
.delta. 7.96 (d, 1H), 7.83 (s, 1H), 7.28-7.33 (m, 3H), 7.16-7.25
(m, 4H), 6.82-6.85 (m, 2H), 5.31 (s, 2H), 4.33 (s, 2H), 3.97-4.08
(m, 3H), 2.64 (q, 2H), 1.39 (t, 3H), 1.23 (t, 3H); 13C NMR in
CDCl3: .delta. 158.8, 143.5, 143.3, 141.7, 136.1, 136.0, 133.8,
129.2, 128.2, 127.9, 127.6, 114.8, 109.8, 63.5, 48.9, 46.6, 28.5,
15.6, 14.8; Mass Spec: 387.3 (M + H).sup.+ 3-[(4-
ethoxyphenyl)methyl]- N-[(4-ethylphenyl)- methyl]imidazo[4,5-
b]pyridin-6-amine 63 ##STR00068## C.sub.25H.sub.26N.sub.2O 1H NMR
in CDCl3: .delta. 7.24-7.38 (m, 5H), 7.16-7.19 (m, 3H), 6.96-7.01
(m, 2H), 6.89 (d, 1H), 6.64 (dd, 1H), 6.46 (dd, 1H), 4.34 (s, 2H),
4.07 (q, 2H), 3.82 (bs, 1H), 2.64 (q, 2H), 1.45 (t, 3H), 1.24 (t,
3H); 13C NMR in CDCl3: .delta. 157.2, 143.1, 142.7, 137.2, 133.1,
130.6, 129.9, 128.2, 128.1, 127.7, 125.4, 115.2, 112.1, 111.1,
102.4, 102.0, 63.8, 49.4, 28.5, 15.7, 14.9; Mass Spec: 371.1 (M +
H).sup.+ 1-(4-ethoxyphenyl)-N- [(4-ethylphenyl)-
methyl]indol-5-amine 64 ##STR00069## C.sub.25H.sub.26N.sub.2O 1H
NMR in CDCl3: .delta. 7.83 (bs, 1H), 7.65 (d, 1H), 7.51-7.56 (m,
2H), 7.32 (d, 2H), 7.17 (d, 2H), 7.05 (d, 1H), 6.93-6.98 (m, 2H),
6.57-6.63 (m, 2H), 4.34 (s, 2H), 4.07 (q, 2H), 2.64 (q, 2H), 1.43
(t, 3H), 1.24 (t, 3H); 13C NMR in CDCl3: .delta. 157.4, 145.0,
143.4, 138.4, 137.0, 128.6, 128.5, 128.3, 127.8, 120.6, 118.7,
118.2, 115.0, 110.4, 93.6, 63.8, 49.2, 28.9, 16.1, 15.3; Mass Spec:
371.1 (M + H).sup.+ 3-(4-ethoxyphenyl)-N- [(4-ethylphenyl)-
methyl]-1H-indol-6- amine 65 ##STR00070## C.sub.24H.sub.25N.sub.3O
1H NMR in CDCl3: .delta. 7.95 (bs, 1H), 7.15- 7.39 (m, 7H), 6.98
(d, 2H), 6.54 (bs, 1H), 6.25 (d, 1H), 4.49 (bs, 1H), 4.30 (s, 2H),
4.07 (q, 2H), 2.62 (q, 2H), 1.44 (t, 3H), 1.22 (t, 3H); 13C NMR in
CDCl3: .delta. 158.5, 145.2, 143.6, 135.3, 129.2, 128.6, 128.2,
128.1, 127.6, 127.2, 123.6, 122.1, 115.1, 106.4, 92.4, 63.6, 47.6,
28.5, 15.6, 14.8; Mass Spec: 372.0 (M + H).sup.+
3-(4-ethoxyphenyl)-N- [(4-ethylphenyl)- methyl]imidazo[1,2-
a]pyridin-7-amine 66 ##STR00071## C.sub.24H.sub.25N.sub.3O 1H NMR
in CDCl3: .delta. 7.92 (d, 1H), 7.55- 7.59 (m, 2H), 7.31-7.35 (m,
3H), 7.17-7.20 (m, 3H), 6.99-7.03 (m, 2H), 6.41 (d, 1H), 4.34 (s,
2H), 4.07 (q, 2H), 2.64 (q, 2H), 1.44 (t, 3H), 1.23 (t, 3H); 13C
NMR in CDCl3: .delta. 157.1, 143.4, 142.5, 139.5, 136.4, 133.3,
131.8, 128.2, 128.1, 127.7, 125.1, 121.5, 115.2, 111.0, 100.0,
63.8, 49.2, 28.5, 15.6, 14.9; Mass Spec: 372.3 (M + H).sup.+
1-(4-ethoxyphenyl)-N- [(4-ethylphenyl)- methyl]pyrrolo[2,3-
b]pyridin-5-amine 67 ##STR00072## C.sub.24H.sub.25N.sub.3O.sub.2 1H
NMR in CD3OD: .delta. 8.78 (s, 1H), 7.45- 7.50 (m, 2H), 7.27-7.31
(m, 3H), 7.08-7.15 (m, 4H), 6.96 (dd, 1H), 6.83 (d, 1H), 4.36 (s,
2H), 4.11 (q, 2H), 2.59 (q, 2H), 1.42 (t, 3H), 1.19 (t, 3H); 13C
NMR in CDCl3: .delta. 159.5, 147.4, 142.8, 136.3, 133.3, 127.6,
127.1, 127.0, 125.6, 121.8, 116.4, 115.4, 112.2, 91.2, 63.6, 28.1,
14.8, 13.6; Mass Spec: 388.2 (M + H).sup.+ 1-(4-ethoxyphenyl)-N-
[(4-ethylphenyl)- methyl]-3-oxido- benzimidazol-3-ium-5- amine
The method of the present invention is for the treatment or
prophylaxis of a viral infection or disease associated therewith,
comprising administering in a therapeutically effective amount to a
mammal in need thereof, a compound of Formula I or II described
above.
Preferably, the mammal is a human and the viral infection is an
arenavirus infection. More preferably, the arenavirus virus is
selected from the group consisting of Lassa, Junin, Machupo,
Guanarito, Sabia, Whitewater Arroyo, Chapare, LCMV, LCMV-like
viruses such as Dandenong, Tacaribe, and Pichinde.
Preferably, the viral infection is associated with a condition
selected from the group consisting of Lassa fever, Argentine
hemorrhagic fever, Bolivian hemorrhagic fever, and Venezuelan
hemorrhagic fever. Most preferably, the viral infection is
associated with Lassa fever.
The method of the present invention may also comprise
co-administration of: a) other antivirals such as ribavirin or
cidofovir; b) vaccines; and/or c) interferons or pegylated
interferons.
Definitions
In accordance with this detailed description, the following
abbreviations and definitions apply. It must be noted that as used
herein, the singular forms "a," "an," and "the" include plural
referents unless the context clearly dictates otherwise.
The publications discussed herein are provided solely for their
disclosure. Nothing herein is to be construed as an admission
regarding antedating the publications. Further, the dates of
publication provided may be different from the actual publication
dates, which may need to be independently confirmed.
Where a range of values is provided, it is understood that each
intervening value is encompassed. The upper and lower limits of
these smaller ranges may independently be included in the smaller,
subject to any specifically-excluded limit in the stated range.
Where the stated range includes one or both of the limits, ranges
excluding either both of those included limits are also included in
the invention. Also contemplated are any values that fall within
the cited ranges.
Unless defined otherwise, all technical and scientific terms used
herein have the same meaning as commonly understood by one of
ordinary skill in the art. Any methods and materials similar or
equivalent to those described herein can also be used in practice
or testing. All publications mentioned herein are incorporated
herein by reference to disclose and describe the methods and/or
materials in connection with which the publications are cited.
By "patient" or "subject" is meant to include any mammal. A
"mammal," for purposes of treatment, refers to any animal
classified as a mammal, including but not limited to, humans,
experimental animals including rats, mice, and guinea pigs,
domestic and farm animals, and zoo, sports, or pet animals, such as
dogs, horses, cats, cows, and the like.
The term "efficacy" as used herein refers to the effectiveness of a
particular treatment regime. Efficacy can be measured based on
change of the course of the disease in response to an agent.
The term "success" as used herein in the context of a chronic
treatment regime refers to the effectiveness of a particular
treatment regime. This includes a balance of efficacy, toxicity
(e.g., side effects and patient tolerance of a formulation or
dosage unit), patient compliance, and the like. For a chronic
administration regime to be considered "successful" it must balance
different aspects of patient care and efficacy to produce a
favorable patient outcome.
The terms "treating," "treatment," and the like are used herein to
refer to obtaining a desired pharmacological and physiological
effect. The effect may be prophylactic in terms of preventing or
partially preventing a disease, symptom, or condition thereof
and/or may be therapeutic in terms of a partial or complete cure of
a disease, condition, symptom, or adverse effect attributed to the
disease. The term "treatment," as used herein, covers any treatment
of a disease in a mammal, such as a human, and includes: (a)
preventing the disease from occurring in a subject which may be
predisposed to the disease but has not yet been diagnosed as having
it, i.e., causing the clinical symptoms of the disease not to
develop in a subject that may be predisposed to the disease but
does not yet experience or display symptoms of the disease; (b)
inhibiting the disease, i.e., arresting or reducing the development
of the disease or its clinical symptoms; and (c) relieving the
disease, i.e., causing regression of the disease and/or its
symptoms or conditions. Treating a patient's suffering from disease
related to pathological inflammation is contemplated. Preventing,
inhibiting, or relieving adverse effects attributed to pathological
inflammation over long periods of time and/or are such caused by
the physiological responses to inappropriate inflammation present
in a biological system over long periods of time are also
contemplated.
As used herein, "acyl" refers to the groups H--C(O)--,
alkyl-C(O)--, substituted alkyl-C(O)--, alkenyl-C(O)--, substituted
alkenyl-C(O)--, alkynyl-C(O)--, substituted alkynyl-C(O)--,
cycloalkylC-(O)--, substituted cycloalkyl-C(O)--, aryl-C(O)--,
substituted aryl-C(O)--, heteroaryl-C(O)--, substituted
heteroaryl-C(O), heterocyclic-C(O)--, and substituted
heterocyclic-C(O)-- wherein alkyl, substituted alkyl, alkenyl,
substituted alkenyl, alkynyl, substituted alkynyl, cycloalkyl,
substituted cycloalkyl, aryl, substituted aryl, heteroaryl,
substituted heteroaryl, heterocyclic and substituted heterocyclic
are as defined herein.
"Alkylamino" refers to the group --NRR where each R is
independently selected from the group consisting of hydrogen,
alkyl, substituted alkyl, alkenyl, substituted alkenyl, alkynyl,
substituted alkynyl, aryl, substituted aryl, cycloalkyl,
substituted cycloalkyl, heteroaryl, substituted heteroaryl,
heterocyclic, substituted heterocyclic and where each R is joined
to form together with the nitrogen atom a heterocyclic or
substituted heterocyclic ring wherein alkyl, substituted alkyl,
alkenyl, substituted alkenyl, alkynyl, substituted alkynyl,
cycloalkyl, substituted cycloalkyl, aryl, substituted aryl,
heteroaryl, substituted heteroaryl, heterocyclic and substituted
heterocyclic are as defined herein.
"Alkenyl" refers to alkenyl group preferably having from 2 to 10
carbon atoms and more preferably 2 to 6 carbon atoms and having at
least 1 and preferably from 1-2 sites of alkenyl unsaturation.
"Alkoxy" refers to the group "alkyl-O--" which includes, by way of
example, methoxy, ethoxy, n-propoxy, isopropoxy, n-butoxy,
tert-butoxy, sec-butoxy, n-pentoxy, n-hexoxy, 1,2-dimethylbutoxy,
and the like.
"Alkyl" refers to linear or branched alkyl groups having from 1 to
10 carbon atoms, alternatively 1 to 6 carbon atoms. This term is
exemplified by groups such as methyl, t-butyl, n-heptyl, octyl and
the like.
"Amino" refers to the group --NH.sub.2.
"Aryl" or "Ar" refers to an unsaturated aromatic carbocyclic group
of from 6 to 14 carbon atoms having a single ring (e.g., phenyl) or
multiple condensed rings (e.g., naphthyl or anthryl) which
condensed rings may or may not be aromatic (e.g.,
2-benzoxazolinone, 2H-1,4-benzoxazin-3(4H)-one, and the like)
provided that the point of attachment is through an aromatic ring
atom.
"Substituted aryl" refers to aryl groups which are substituted with
from 1 to 3 substituents selected from the group consisting of
hydroxy, acyl, acylamino, thiocarbonylamino, acyloxy, alkyl,
substituted alkyl, haloalkyl, hydroxyalkyl, alkoxy, substituted
alkoxy, alkenyl, substituted alkenyl, alkynyl, substituted alkynyl,
amidino, alkylamidino, thioamidino, amino, aminoacyl,
aminocarbonyloxy, aminocarbonylamino, aminothiocarbonylamino, aryl,
substituted aryl, aryloxy, substituted aryloxy, cycloalkoxy,
substituted cycloalkoxy, heteroaryloxy, oxetane, substituted
heteroaryloxy, heterocyclyloxy, substituted heterocyclyloxy,
carboxyl, carboxylalkyl, carboxyl-substituted alkyl,
carboxyl-cycloalkyl, carboxyl-substituted cycloalkyl, carboxylaryl,
carboxyl-substituted aryl, carboxylheteroaryl, carboxyl-substituted
heteroaryl, carboxylheterocyclic, carboxyl-substituted
heterocyclic, carboxylamido, cyano, thiol, thioalkyl, substituted
thioalkyl, thioaryl, substituted thioaryl, thioheteroaryl,
substituted thioheteroaryl, thiocycloalkyl, substituted
thiocycloalkyl, thioheterocyclic, substituted thioheterocyclic,
cycloalkyl, substituted cycloalkyl, guanidino, guanidinosulfone,
halo, nitro, heteroaryl, substituted heteroaryl, heterocyclic,
substituted heterocyclic, cycloalkoxy, substituted cycloalkoxy,
heteroaryloxy, substituted heteroaryloxy, heterocyclyloxy,
substituted heterocyclyloxy, oxycarbonylamino,
oxythiocarbonylamino, --S(O).sub.2-alkyl, --S(O).sub.2-substituted
alkyl, --S(O).sub.2-cycloalkyl, --S(O).sub.2-substituted
cycloalkyl, --S(O).sub.2-alkenyl, --S(O).sub.2-substituted alkenyl,
--S(O).sub.2-aryl, --S(O).sub.2-substituted aryl,
--S(O).sub.2-heteroaryl, --S(O).sub.2-substituted heteroaryl,
--S(O).sub.2-heterocyclic, --S(O).sub.2-substituted heterocyclic,
--OS(O).sub.2-alkyl, --OS(O).sub.2-substituted alkyl,
--OS(O).sub.2-aryl, --OS(O).sub.2-substituted aryl,
--OS(O).sub.2-heteroaryl, --OS(O).sub.2-substituted heteroaryl,
--OS(O).sub.2-heterocyclic, --OS(O).sub.2-substituted heterocyclic,
--OS(O).sub.2--NRR where R is hydrogen. or alkyl, --NRS(O).sub.2--
alkyl, --NRS(O).sub.2-substituted alkyl, --NRS(O).sub.2-aryl,
--NRS(O).sub.2-substituted aryl, --NRS(O).sub.2-heteroaryl,
--NRS(O).sub.2-substituted heteroaryl, --NRS(O).sub.2-heterocyclic,
--NRS(O).sub.2-substituted heterocyclic, --NRS(O).sub.2--NR-alkyl,
--NRS(O).sub.2--NR-substituted alkyl, --NRS(O).sub.2--NR-aryl,
--NRS(O).sub.2--NR-substituted aryl, --NRS(O).sub.2--NR-heteroaryl,
--NRS(O).sub.2--NR-substituted heteroaryl,
--NRS(O).sub.2--NR-heterocyclic, --NRS(O).sub.2--NR-substituted
heterocyclic where R is hydrogen or alkyl, mono- and di-alkylamino,
mono- and di-(substituted alkyl)amino, mono- and di-arylamino,
mono- and di-substituted arylamino, mono- and di-heteroarylamino,
mono- and di-substituted heteroarylamino, mono- and di-heterocyclic
amino, mono- and di-substituted heterocyclic amino, unsymmetric
di-substituted amines having different substituents independently
selected from the group consisting of alkyl, substituted alkyl,
aryl, substituted aryl, heteroaryl, substituted heteroaryl,
heterocyclic and substituted heterocyclic and amino groups on the
substituted aryl blocked by conventional blocking groups such as
Boc, Cbz, formyl, and the like or substituted with --SO.sub.2NRR
where R is hydrogen or alkyl.
"Cycloalkyl" refers to cyclic alkyl groups of from 3 to 8 carbon
atoms having a single cyclic ring including, by way of example,
cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cyclooctyl and
the like. Excluded from this definition are multi-ring alkyl groups
such as adamantanyl, etc.
"Halo" or "halogen" refers to fluoro, chloro, bromo and iodo.
"Heteroaryl" refers to an aromatic carbocyclic group of from 2 to
10 carbon atoms and 1 to 4 heteroatoms selected from the group
consisting of oxygen, nitrogen and sulfur within the ring or oxides
thereof. Such heteroaryl groups can have a single ring (e.g.,
pyridyl or furyl) or multiple condensed rings (e.g., indolizinyl or
benzothienyl) wherein one or more of the condensed rings may or may
not be aromatic provided that the point of attachment is through an
aromatic ring atom. Additionally, the heteroatoms of the heteroaryl
group may be oxidized, i.e., to form pyridine N-oxides or
1,1-dioxo-1,2,5-thiadiazoles and the like. Additionally, the carbon
atoms of the ring may be substituted with an oxo (.dbd.O). The term
"heteroaryl having two nitrogen atoms in the heteroaryl, ring"
refers to a heteroaryl group having two, and only two, nitrogen
atoms in the heteroaryl ring and optionally containing 1 or 2 other
heteroatoms in the heteroaryl ring, such as oxygen or sulfur.
"Substituted heteroaryl" refers to heteroaryl groups which are
substituted with from 1 to 3 substituents selected from the group
consisting of hydroxy, acyl, acylamino, thiocarbonylamino, acyloxy,
alkyl, substituted alkyl, alkoxy, substituted alkoxy, alkenyl,
substituted alkenyl, alkynyl, substituted alkynyl, amidino,
alkylamidino, thioamidino, amino, aminoacyl, aminocarbonyloxy,
aminocarbonylamino, aminothiocarbonylamino, aryl, substituted aryl,
aryloxy, substituted aryloxy, cycloalkoxy, substituted cycloalkoxy,
heteroaryloxy, substituted heteroaryloxy, heterocyclyloxy,
substituted heterocyclyloxy, carboxyl, carboxylalkyl,
carboxyl-substituted alkyl, carboxyl-cycloalkyl,
carboxyl-substituted cycloalkyl, carboxylaryl, carboxyl-substituted
aryl, carboxylheteroaryl, carboxyl-substituted heteroaryl,
carboxylheterocyclic, carboxyl-substituted heterocyclic,
carboxylamido, cyano, thiol, thioalkyl, substituted thioalkyl,
thioaryl, substituted thioaryl, thioheteroaryl, substituted
thioheteroaryl, thiocycloalkyl, substituted thiocycloalkyl,
thioheterocyclic, substituted thioheterocyclic, cycloalkyl,
substituted cycloalkyl, guanidino, guanidinosulfone, halo, nitro,
heteroaryl, substituted heteroaryl, heterocyclic, substituted
heterocyclic, cycloalkoxy, substituted cycloalkoxy, heteroaryloxy,
substituted heteroaryloxy, heterocyclyloxy, substituted
heterocyclyloxy, oxycarbonylamino, oxythiocarbonylamino,
--S(O).sub.2-alkyl, --S(O).sub.2-substituted alkyl,
--S(O).sub.2-cycloalkyl, --S(O).sub.2-substituted cycloalkyl,
--S(O).sub.2-alkenyl, --S(O).sub.2-substituted alkenyl,
--S(O).sub.2-aryl, --S(O).sub.2-substituted aryl,
--S(O).sub.2-heteroaryl, --S(O).sub.2-substituted heteroaryl,
--S(O).sub.2-heterocyclic, --S(O).sub.2-substituted heterocyclic,
--OS(O).sub.2-alkyl, --OS(O).sub.2-substituted alkyl,
--OS(O).sub.2-aryl, --OS(O).sub.2-substituted aryl,
--OS(O).sub.2-heteroaryl, --OS(O).sub.2-substituted heteroaryl,
--OS(O).sub.2-heterocyclic, --OS(O).sub.2-substituted heterocyclic,
--OSO.sub.2--NRR where R is hydrogen or alkyl,
--NRS(O).sub.2-alkyl, --NRS(O).sub.2-substituted alkyl,
--NRS(O).sub.2-aryl, --NRS(O).sub.2-substituted aryl,
--NRS(O).sub.2-heteroaryl, --NRS(O).sub.2-substituted heteroaryl,
--NRS(O).sub.2-heterocyclic, --NRS(O).sub.2-substituted
heterocyclic, --NRS(O).sub.2--NR-alkyl,
--NRS(O).sub.2--NR-substituted alkyl, --NRS(O).sub.2--NR-aryl,
--NRS(O).sub.2--NR-substituted aryl, --NRS(O).sub.2--NR-heteroaryl,
--NRS(O).sub.2--NR-substituted heteroaryl,
--NRS(O).sub.2--NR-heterocyclic, --NRS(O).sub.2--NR-substituted
heterocyclic where R is hydrogen or alkyl, mono- and di-alkylamino,
mono- and di-(substituted alkyl)amino, mono- and di-arylamino,
mono- and di-substituted arylamino, mono- and di-heteroarylamino,
mono- and di-substituted heteroarylamino, mono- and di-heterocyclic
amino, mono- and di-substituted heterocyclic amino, unsymmetric
di-substituted amines having different substituents independently
selected from the group consisting of alkyl, substituted alkyl,
aryl, substituted aryl, heteroaryl, substituted heteroaryl,
heterocyclic and substituted heterocyclic and amino groups on the
substituted aryl blocked by conventional blocking groups such as
Boc, Cbz, formyl, and the like or substituted with --SO.sub.2NRR
where R is hydrogen or alkyl.
"Sulfonyl" refers to the group --S(O).sub.2R where R is selected
from the group consisting of hydrogen, alkyl, substituted alkyl,
alkenyl, substituted alkenyl, alkynyl, substituted alkynyl, aryl,
substituted aryl, cycloalkyl, substituted cycloalkyl, heteroaryl,
substituted heteroaryl, heterocyclic, substituted heterocyclic
wherein alkyl, substituted alkyl, alkenyl, substituted alkenyl,
alkynyl, substituted alkynyl, cycloalkyl, substituted cycloalkyl,
aryl, substituted aryl, heteroaryl, substituted heteroaryl,
heterocyclic and substituted heterocyclic are as defined
herein.
"Optionally substituted" means that the recited group may be
unsubstituted or the recited group may be substituted.
"Pharmaceutically-acceptable carrier" means a carrier that is
useful in preparing a pharmaceutical composition or formulation
that is generally safe, non-toxic, and neither biologically nor
otherwise undesirable, and includes a carrier that is acceptable
for veterinary use as well as human pharmaceutical use.
"Pharmaceutically-acceptable cation" refers to the cation of a
pharmaceutically-acceptable salt.
"Pharmaceutically-acceptable salt" refers to salts which retain the
biological effectiveness and properties of compounds which are not
biologically or otherwise undesirable. Pharmaceutically-acceptable
salts refer to pharmaceutically-acceptable salts of the compounds,
which salts are derived from a variety of organic and inorganic
counter ions well known in the art and include, by way of example
only, sodium, potassium, calcium, magnesium, ammonium,
tetraalkylammonium, and the like; and when the molecule contains a
basic functionality, salts of organic or inorganic acids, such as
hydrochloride, hydrobromide, tartrate, mesylate, acetate, maleate,
oxalate and the like.
Pharmaceutically-acceptable base addition salts can be prepared
from inorganic and organic bases. Salts derived from inorganic
bases include, by way of example only, sodium, potassium, lithium,
ammonium, calcium and magnesium salts. Salts derived from organic
bases include, but are not limited to, salts of primary, secondary
and tertiary amines, such as alkyl amines, dialkyl amines, trialkyl
amines, substituted alkyl amines, di(substituted alkyl) amines,
tri(substituted alkyl) amines, alkenyl amines, dialkenyl amines,
trialkenyl amines, substituted alkenyl amines, di(substituted
alkenyl) amines, tri(substituted alkenyl) amines, cycloalkyl
amines, di(cycloalkyl) amines, tri(cycloalkyl) amines, substituted
cycloalkyl amines, disubstituted cycloalkyl amine, trisubstituted
cycloalkyl amines, cycloalkenyl amines, di(cycloalkenyl) amines,
tri(cycloalkenyl) amines, substituted cycloalkenyl amines,
disubstituted cycloalkenyl amine, trisubstituted cycloalkenyl
amines, aryl amines, diaryl amines, triaryl amines, heteroaryl
amines, diheteroaryl amines, triheteroaryl amines, heterocyclic
amines, diheterocyclic amines, triheterocyclic amines, mixed di-
and tri-amines where at least two of the substituents on the amine
are different and are selected from the group consisting of alkyl,
substituted alkyl, alkenyl, substituted alkenyl, cycloalkyl,
substituted cycloalkyl, cycloalkenyl, substituted cycloalkenyl,
aryl, heteroaryl, heterocyclic, and the like. Also included are
amines where the two or three substituents, together with the amino
nitrogen, form a heterocyclic or heteroaryl group.
Examples of suitable amines include, by way of example only,
isopropylamine, trimethyl amine, diethyl amine, tri(iso-propyl)
amine, tri(n-propyl) amine, ethanolamine, 2-dimethylaminoethanol,
tromethamine, lysine, arginine, histidine, caffeine, procaine,
hydrabamine, choline, betaine, ethylenediamine, glucosamine,
N-alkylglucamines, theobromine, purines, piperazine, piperidine,
morpholine, N-ethylpiperidine, and the like. It should also be
understood that other carboxylic acid derivatives would be useful,
for example, carboxylic acid amides, including carboxamides, lower
alkyl carboxamides, dialkyl carboxamides, and the like.
Pharmaceutically-acceptable acid addition salts may be prepared
from inorganic and organic acids. Salts derived from inorganic
acids include hydrochloric acid, hydrobromic acid, sulfuric acid,
nitric acid, phosphoric acid, and the like. Salts derived from
organic acids include acetic acid, propionic acid, glycolic acid,
pyruvic acid, oxalic acid, malic acid, malonic acid, succinic acid,
maleic acid, fumaric acid, tartaric acid, citric acid, benzoic
acid, cinnamic acid, mandelic acid, methanesulfonic acid,
ethanesulfonic acid, p-toluene-sulfonic acid, salicylic acid, and
the like.
A compound may act as a pro-drug. Pro-drug means any compound which
releases an active parent drug in vivo when such pro-drug is
administered to a mammalian subject. Pro-drugs are prepared by
modifying functional groups present in such a way that the
modifications may be cleaved in vivo to release the parent
compound. Pro-drugs include compounds wherein a hydroxy, amino, or
sulfhydryl group is bonded to any group that may be cleaved in vivo
to regenerate the free hydroxyl, amino, or sulfhydryl group,
respectively. Examples of pro-drugs include, but are not limited to
esters (e.g., acetate, formate, and benzoate derivatives),
carbamates (e.g., N,N-dimethylamino-carbonyl) of hydroxy functional
groups, and the like.
"Treating" or "treatment" of a disease includes:
(1) preventing the disease, i.e. causing the clinical symptoms of
the disease not to develop in a mammal that may be exposed to or
predisposed to the disease but does not yet experience or display
symptoms of the disease,
(2) inhibiting the disease, i.e., arresting or reducing the
development of the disease or its clinical symptoms, or
(3) relieving the disease, i.e., causing regression of the disease
or its clinical symptoms.
A "therapeutically-effective amount" means the amount of a compound
that, when administered to a mammal for treating a disease, is
sufficient to effect such treatment for the disease. The
"therapeutically-effective amount" will vary depending on the
compound, the disease, and its severity and the age, weight, etc.,
of the mammal to be treated.
Synthesis of Compounds
The compounds are readily prepared via several divergent synthetic
routes with the particular route selected relative to the ease of
compound preparation, the commercial availability of starting
materials, and the like.
The compounds can be prepared from readily-available starting
materials using the following general methods and procedures. It
will be appreciated that where process conditions (i.e., reaction
temperatures, times, mole ratios of reactants, solvents, pressures,
etc.) are given, other process conditions can also be used unless
otherwise stated. Optimum reaction conditions may vary with the
particular reactants or solvent used, but such conditions can be
determined by one skilled in the art by routine optimization
procedures.
Additionally, as will be apparent to those skilled in the art,
conventional protecting groups may be necessary to prevent certain
functional groups from undergoing undesired reactions. Suitable
protecting groups for various functional groups as well as suitable
conditions for protecting and deprotecting particular functional
groups are well known in the art. For example, numerous protecting
groups are described in T. W. Greene and G. M. Wuts, Protecting
Groups in Organic Synthesis, Second Edition, Wiley, New York, 1991,
and references cited therein.
Furthermore, the compounds may contain one or more chiral centers.
Accordingly, if desired, such compounds can be prepared or isolated
as pure stereoisomers, i.e., as individual enantiomers or
diastereomers, or as stereoisomer-enriched mixtures. All such
stereoisomers (and enriched mixtures) are included unless otherwise
indicated. Pure stereoisomers (or enriched mixtures) may be
prepared using, for example, optically-active starting materials or
stereoselective reagents well-known in the art. Alternatively,
racemic mixtures of such compounds can be separated using, for
example, chiral column chromatography, chiral resolving agents, and
the like.
Unless otherwise indicated, if the products contain chiral centers,
they are a mixture of R, S enantiomers. However, when a chiral
product is desired, the chiral product can be obtained via
purification techniques which separate enantiomers from a R, S
mixture to provide for one or the other stereoisomer. Such
techniques are known in the art.
The compounds can be provided as pro-drugs which convert (e.g.,
hydrolyze, metabolize, etc.) in vivo to a compound above.
Pharmaceutical Formulations of the Compounds
In general, compounds will be administered in a
therapeutically-effective amount by any of the accepted modes of
administration for these compounds. The compounds can be
administered by a variety of routes, including, but not limited to,
oral, parenteral (e.g., subcutaneous, subdural, intravenous,
intramuscular, intrathecal, intraperitoneal, intracerebral,
intraarterial, or intralesional routes of administration), topical,
intranasal, localized (e.g., surgical application or surgical
suppository), rectal, and pulmonary (e.g., aerosols, inhalation, or
powder). Accordingly, these compounds are effective as both
injectable and oral compositions. The compounds can be administered
continuously by infusion or by bolus injection.
The actual amount of the compound, i.e., the active ingredient,
will depend on a number of factors, such as the severity of the
disease, i.e., the condition or disease to be treated, age, and
relative health of the subject, the potency of the compound used,
the route and form of administration, and other factors.
Toxicity and therapeutic efficacy of such compounds can be
determined by standard pharmaceutical procedures in cell cultures
or experimental animals, e.g., for determining the LD.sub.50 (the
dose lethal to 50% of the population) and the ED.sub.50 (the dose
therapeutically effective in 50% of the population). The dose ratio
between toxic and therapeutic effects is the therapeutic index and
it can be expressed as the ratio LD.sub.50/ED.sub.50.
The data obtained from the cell culture assays and animal studies
can be used in formulating a range of dosage for use in humans. The
dosage of such compounds lies within a range of circulating
concentrations that include the ED.sub.50 with little or no
toxicity. The dosage may vary within this range depending upon the
dosage form employed and the route of administration utilized. For
any compound used, the therapeutically-effective dose can be
estimated initially from cell culture assays. A dose may be
formulated in animal models to achieve a circulating plasma
concentration range which includes the IC.sub.50 (i.e., the
concentration of the test compound which achieves a half-maximal
inhibition of symptoms) as determined in cell culture. Such
information can be used to more accurately determine useful doses
in humans. Levels in plasma may be measured, for example, by high
performance liquid chromatography.
The amount of the pharmaceutical composition administered to the
patient will vary depending upon what is being administered, the
purpose of the administration, such as prophylaxis or therapy, the
state of the patient, the manner of administration, and the like.
In therapeutic applications, compositions are administered to a
patient already suffering from a disease in an amount sufficient to
cure or at least partially arrest the symptoms of the disease and
its complications. An amount adequate to accomplish this is defined
as "therapeutically-effective dose." Amounts effective for this use
will depend on the disease condition being treated as well as by
the judgment of the attending clinician depending upon factors such
as the severity of the inflammation, the age, weight, and general
condition of the patient, and the like.
The compositions administered to a patient are in the form of 24
pharmaceutical compositions described supra. These compositions may
be sterilized by conventional sterilization techniques, or may be
sterile filtered. The resulting aqueous solutions may be packaged
for use as is, or lyophilized, the lyophilized preparation being
combined with a sterile aqueous carrier prior to administration. It
will be understood that use of certain of the foregoing excipients,
carriers, or stabilizers will result in the formation of
pharmaceutical salts.
The active compound is effective over a wide dosage range and is
generally administered in a pharmaceutically- or
therapeutically-effective amount. The therapeutic dosage of the
compounds will vary according to, for example, the particular use
for which the treatment is made, the manner of administration of
the compound, the health and condition of the patient, and the
judgment of the prescribing physician. For example, for intravenous
administration, the dose will typically be in the range of about
0.5 mg to about 100 mg per kilogram body weight. Effective doses
can be extrapolated from dose-response curves derived from in vitro
or animal model test systems. Typically, the clinician will
administer the compound until a dosage is reached that achieves the
desired effect.
When employed as pharmaceuticals, the compounds are usually
administered in the form of pharmaceutical compositions.
Pharmaceutical compositions contain as the active ingredient one or
more of the compounds above, associated with one or more
pharmaceutically-acceptable carriers or excipients. The excipient
employed is typically one suitable for administration to human
subjects or other mammals. In making the compositions, the active
ingredient is usually mixed with an excipient, diluted by an
excipient, or enclosed within a carrier which can be in the form of
a capsule, sachet, paper or other container. When the excipient
serves as a diluent, it can be a solid, semi-solid, or liquid
material, which acts as a vehicle, carrier, or medium for the
active ingredient. Thus, the compositions can be in the form of
tablets, pills, powders, lozenges, sachets, cachets, elixirs,
suspensions, emulsions, solutions, syrups, aerosols (as a solid or
in a liquid medium), ointments containing, for example, up to 10%
by weight of the active compound, soft and hard gelatin capsules,
suppositories, sterile injectable solutions, and sterile packaged
powders.
In preparing a formulation, it may be necessary to mill the active
compound to provide the appropriate particle size prior to
combining with the other ingredients. If the active compound is
substantially insoluble, it ordinarily is milled to a particle size
of less than 200 mesh. If the active compound is substantially
water soluble, the particle size is normally adjusted by milling to
provide a substantially uniform distribution in the formulation,
e.g., about 40 mesh.
Some examples of suitable excipients include lactose, dextrose,
sucrose, sorbitol, mannitol, starches, gum acacia, calcium
phosphate, alginates, tragacanth, gelatin, calcium silicate,
microcrystalline cellulose, polyvinylpyrrolidone, cellulose,
sterile water, syrup, and methyl cellulose. The formulations can
additionally include: lubricating agents such as talc, magnesium
stearate, and mineral oil; wetting agents; emulsifying and
suspending agents; preserving agents such as methyl- and
propylhydroxy-benzoates; sweetening agents; and flavoring agents.
The compositions of the invention can be formulated so as to
provide quick, sustained, or delayed-release of the active
ingredient after administration to the patient by employing
procedures known in the art.
The quantity of active compound in the pharmaceutical composition
and unit dosage form thereof may be varied or adjusted widely
depending upon the particular application, the manner or
introduction, the potency of the particular compound, and the
desired concentration. The term "unit dosage forms" refers to
physically-discrete units suitable as unitary dosages for human
subjects and other mammals, each unit containing a predetermined
quantity of active material calculated to produce the desired
therapeutic effect, in association with a suitable pharmaceutical
excipient.
The compound can be formulated for parenteral administration in a
suitable inert carrier, such as a sterile physiological saline
solution. The dose administered will be determined by route of
administration.
Administration of therapeutic agents by intravenous formulation is
well known in the pharmaceutical industry. An intravenous
formulation should possess certain qualities aside from being just
a composition in which the therapeutic agent is soluble. For
example, the formulation should promote the overall stability of
the active ingredient(s), also, the manufacture of the formulation
should be cost-effective. All of these factors ultimately determine
the overall success and usefulness of an intravenous
formulation.
Other accessory additives that may be included in pharmaceutical
formulations and compounds as follow: solvents: ethanol, glycerol,
propylene glycol; stabilizers: EDTA (ethylene diamine tetraacetic
acid), citric acid; antimicrobial preservatives: benzyl alcohol,
methyl paraben, propyl paraben; buffering agents: citric
acid/sodium citrate, potassium hydrogen tartrate, sodium hydrogen
tartrate, acetic acid/sodium acetate, maleic acid/sodium maleate,
sodium hydrogen phthalate, phosphoric acid/potassium dihydrogen
phosphate, phosphoric acid/disodium hydrogen phosphate; and
tonicity modifiers: sodium chloride, mannitol, dextrose.
The presence of a buffer is necessary to maintain the aqueous pH in
the range of from about 4 to about 8. The buffer system is
generally a mixture of a weak acid and a soluble salt thereof,
e.g., sodium citrate/citric acid; or the monocation or dication
salt of a dibasic acid, e.g., potassium hydrogen tartrate; sodium
hydrogen tartrate, phosphoric acid/potassium dihydrogen phosphate,
and phosphoric acid/disodium hydrogen phosphate.
The amount of buffer system used is dependent on (1) the desired
pH; and (2) the amount of drug. Generally, the amount of buffer
used is able to maintain a formulation pH in the range of 4 to 8.
Generally, a 1:1 to 10:1 mole ratio of buffer (where the moles of
buffer are taken as the combined moles of the buffer ingredients,
e.g., sodium citrate and citric acid) to drug is used.
A useful buffer is sodium citrate/citric acid in the range of 5 to
50 mg per ml. sodium citrate to 1 to 15 mg per ml. citric acid,
sufficient to maintain an aqueous pH of 4-6 of the composition.
The buffer agent may also be present to prevent the precipitation
of the drug through soluble metal complex formation with dissolved
metal ions, e.g., Ca, Mg, Fe, Al, Ba, which may leach out of glass
containers or rubber stoppers or be present in ordinary tap water.
The agent may act as a competitive complexing agent with the drug
and produce a soluble metal complex leading to the presence of
undesirable particulates.
In addition, the presence of an agent, e.g., sodium chloride in an
amount of about of 1-8 mg/ml, to adjust the tonicity to the same
value of human blood may be required to avoid the swelling or
shrinkage of erythrocytes upon administration of the intravenous
formulation leading to undesirable side effects such as nausea or
diarrhea and possibly to associated blood disorders. In general,
the tonicity of the formulation matches that of human blood which
is in the range of 282 to 288 mOsm/kg, and in general is 285
mOsm/kg, which is equivalent to the osmotic pressure corresponding
to a 0.9% solution of sodium chloride.
An intravenous formulation can be administered by direct
intravenous injection, i.v. bolus, or can be administered by
infusion by addition to an appropriate infusion solution such as
0.9% sodium chloride injection or other compatible infusion
solution.
The compositions are preferably formulated in a unit dosage form,
each dosage containing from about 5 to about 100 mg, more usually
about 10 to about 30 mg, of the active ingredient. The term "unit
dosage forms" refers to physically discrete units suitable as
unitary dosages for human subjects and other mammals, each unit
containing a predetermined quantity of active material calculated
to produce the desired therapeutic effect, in association with a
suitable pharmaceutical excipient.
The active compound is effective over a wide dosage range and is
generally administered in a pharmaceutically effective amount. It
will be understood, however, that the amount of the compound
actually administered will be determined by a physician, in the
light of the relevant circumstances, including the condition to be
treated, the chosen route of administration, the actual compound
administered, the age, weight, and response of the individual
patient, the severity of the patient's symptoms, and the like.
For preparing solid compositions such as tablets, the principal
active ingredient is mixed with a pharmaceutical excipient to form
a solid preformulation composition containing a homogeneous mixture
of a compound of the present invention. When referring to these
preformulation compositions as homogeneous, it is meant that the
active ingredient is dispersed evenly throughout the composition so
that the composition may be readily subdivided into equally
effective unit dosage forms such as tablets, pills and capsules.
This solid preformulation is then subdivided into unit dosage forms
of the type described above containing from, for example, 0.1 to
about 2000 mg of the active ingredient.
The tablets or pills may be coated or otherwise compounded to
provide a dosage form affording the advantage of prolonged action.
For example, the tablet or pill can comprise an inner dosage and an
outer dosage component, the latter being in the form of an envelope
over the former. The two components can be separated by an enteric
layer which serves to resist disintegration in the stomach and
permit the inner component to pass intact into the duodenum or to
be delayed in release. A variety of materials can be used for such
enteric layers or coatings, such materials including a number of
polymeric acids and mixtures of polymeric acids with such materials
as shellac, cetyl alcohol, and cellulose acetate.
The liquid forms in which the novel compositions may be
incorporated for administration orally or by injection include
aqueous solutions, suitably flavored syrups, aqueous or oil
suspensions, and flavored emulsions with edible oils such as
cottonseed oil, sesame oil, coconut oil, or peanut oil, as well as
elixirs and similar pharmaceutical vehicles.
Compositions for inhalation or insufflation include solutions and
suspensions in pharmaceutically-acceptable, aqueous or organic
solvents, or mixtures thereof, and powders. The liquid or solid
compositions may contain suitable pharmaceutically-acceptable
excipients as described supra. Compositions in
pharmaceutically-acceptable solvents may be nebulized by use of
inert gases. Nebulized solutions may be breathed directly from the
nebulizing device or the nebulizing device may be attached to a
face masks tent, or intermittent positive pressure breathing
machine. Solution, suspension, or powder compositions may be
administered from devices which deliver the formulation in an
appropriate manner.
The compounds can be administered in a sustained release form.
Suitable examples of sustained-release preparations include
semipermeable matrices of solid hydrophobic polymers containing the
compounds, which matrices are in the form of shaped articles, e.g.,
films, or microcapsules. Examples of sustained-release matrices
include polyesters, hydrogels (e.g.,
poly(2-hydroxyethyl-methacrylate) as described by Langer et al., J.
Biomed. Mater. Res. 15: 167-277 (1981) and Langer, Chem. Tech. 12:
98-105 (1982) or poly(vinyl alcohol)), polylactides (U.S. Pat. No.
3,773,919), copolymers of L-glutamic acid and gamma
ethyl-L-glutamate (Sidman et al., Biopolymers 22: 547-556, 1983),
non-degradable ethylene-vinyl acetate (Langer et al., supra),
degradable lactic acid-glycolic acid copolymers such as the LUPRON
DEPOT.TM. (i.e., injectable microspheres composed of lactic
acid-glycolic acid copolymer and leuprolide acetate), and
poly-D-(-)-3-hydroxybutyric acid (EP 133,988).
The compounds can be administered in a sustained-release form, for
example a depot injection, implant preparation, or osmotic pump,
which can be formulated in such a manner as to permit a
sustained-release of the active ingredient. Implants for
sustained-release formulations are well-known in the art. Implants
may be formulated as, including but not limited to, microspheres,
slabs, with biodegradable or non-biodegradable polymers. For
example, polymers of lactic acid and/or glycolic acid form an
erodible polymer that is well-tolerated by the host.
Transdermal delivery devices ("patches") may also be employed. Such
transdermal patches may be used to provide continuous or
discontinuous infusion of the compounds in controlled amounts. The
construction and use of transdermal patches for the delivery of
pharmaceutical agents is well known in the art. See, e.g., U.S.
Pat. No. 5,023,252, issued Jun. 11, 1991, herein incorporated by
reference. Such patches may be constructed for continuous,
pulsatile, or on-demand delivery of pharmaceutical agents.
Direct or indirect placement techniques may be used when it is
desirable or necessary to introduce the pharmaceutical composition
to the brain. Direct techniques usually involve placement of a drug
delivery catheter into the host's ventricular system to bypass the
blood-brain barrier. One such implantable delivery system used for
the transport of biological factors to specific anatomical regions
of the body is described in U.S. Pat. No. 5,011,472, which is
herein incorporated by reference.
Indirect techniques usually involve formulating the compositions to
provide for drug latentiation by the conversion of hydrophilic
drugs into lipid-soluble drugs. Latentiation is generally achieved
through blocking of the hydroxy, carbonyl, sulfate, and primary
amine groups present on the drug to render the drug more
lipid-soluble and amenable to transportation across the blood-brain
barrier. Alternatively, the delivery of hydrophilic drugs may be
enhanced by intra-arterial infusion of hypertonic solutions which
can transiently open the blood-brain barrier.
In order to enhance serum half-life, the compounds may be
encapsulated, introduced into the lumen of liposomes, prepared as a
colloid, or other conventional techniques may be employed which
provide an extended serum half-life of the compounds. A variety of
methods are available for preparing liposomes, as described in,
e.g., Szoka et al., U.S. Pat. Nos. 4,235,871, 4,501,728 and
4,837,028 each of which is incorporated herein by reference.
Pharmaceutical compositions are suitable for use in a variety of
drug delivery systems. Suitable formulations for use in the present
invention are found in Remington's Pharmaceutical Sciences, Mace
Publishing Company, Philadelphia, Pa., 17th ed. (1985).
The provided compounds and pharmaceutical compositions show
biological activity in treating and preventing viral infections and
associated diseases, and, accordingly, have utility in treating
viral infections and associated diseases, such as hemorrhagic fever
viruses, in mammals including humans.
Hemorrhagic fever viruses (HFVs) are RNA viruses that cause a
variety of disease syndromes with similar clinical characteristics.
HFVs that are of concern as potential biological weapons include
but are not limited to: Arenaviridae (Junin, Machupo, Guanarito,
Sabia, and Lassa), Filoviridae (Ebola and Marburg viruses),
Flaviviridae (yellow fever, Omsk hemorrhagic fever and Kyasanur
Forest disease viruses), and Bunyaviridae (Rift Valley fever and
Crimean-Congo hemorrhagic fever). The naturally-occurring
arenaviruses and potential engineered arenaviruses are included in
the Category A Pathogen list according to the Centers for Disease
Control and Prevention as being among those agents that have
greatest potential for mass casualties.
Risk factors include: travel to Africa or Asia, handling of animal
carcasses, contact with infected animals or people, and/or
arthropod bites. Arenaviruses are highly infectious after direct
contact with infected blood and/or bodily secretions. Humans
usually become infected through contact with infected rodents, the
bite of an infected arthropod, direct contact with animal
carcasses, inhalation of infectious rodent excreta and/or injection
of food contaminated with rodent excreta. The Tacaribe virus has
been associated with bats. Airborne transmission of hemorrhagic
fever is another mode. Person-to-person contact may also occur in
some cases.
All of the hemorrhagic fevers exhibit similar clinical symptoms.
However, in general the clinical manifestations are non-specific
and variable. The incubation period is approximately 7-14 days. The
onset is gradual with fever and malaise, tachypnea, relative
bradycardia, hypotension, circulatory shock, conjunctival
infection, pharyngitis, lymphadenopathy, encephalitis, myalgia,
back pain, headache and dizziness, as well as hyperesthesia of the
skin. Some infected patients may not develop hemorrhagic
manifestations.
Methods of diagnosis at specialized laboratories include antigen
detection by antigen-capture enzyme-linked immunosorbent assay
(ELISA), IgM antibody detection by antibody-capture enzyme-linked
immunosorbent assay, reverse transcriptase polymerase chain
reaction (RT-PCR), and viral isolation. Antigen detection (by
enzyme-linked immunosorbent assay) and reverse transcriptase
polymerase chain reaction are the most useful diagnostic techniques
in the acute clinical setting. Viral isolation is of limited value
because it requires a biosafety level 4 (BSL-4) laboratory.
In the examples below, if an abbreviation is not defined above, it
has its generally accepted meaning. Further, all temperatures are
in degrees Celsius (unless otherwise indicated). The following
Methods were used to prepare the compounds set forth below as
indicated.
Example 1
Formulation 1
Hard gelatin capsules containing the following ingredients are
prepared:
TABLE-US-00003 Quantity Ingredient (mg/capsule) Active Ingredient
30.0 Starch 305.0 Magnesium stearate 5.0
The above ingredients are mixed and filled into hard gelatin
capsules in 340 mg quantities.
Example 2
Formulation 2
A tablet formula is prepared using the ingredients below:
TABLE-US-00004 Quantity Ingredient (mg/capsule) Active ingredient
25.0 Cellulose, microcrystalline 200.0 Colloidal silicon dioxide
10.0 Stearic acid 5.0
The components are blended and compressed to form tablets, each
weighing 240 mg.
Example 3
Formulation 3
A dry powder inhaler formulation is prepared containing the
following components:
TABLE-US-00005 Ingredient Weight % Active Ingredient 5 Lactose
95
The active mixture is mixed with the lactose and the mixture is
added to a dry powder inhaling appliance.
Example 4
Formulation 4
Tablets, each containing 30 mg of active ingredient, are prepared
as follows:
TABLE-US-00006 Quantity Ingredient (mg/capsule) Active Ingredient
30.0 mg Starch 45.0 mg Microcrystalline cellulose 35.0 mg
Polyvinylpyrrolidone 4.0 mg (as 10% solution in water) Sodium
Carboxymethyl starch 4.5 mg Magnesium stearate 0.5 mg Talc 1.0 mg
Total 120 mg
The active ingredient, starch, and cellulose are passed through a
No. 20 mesh U.S. sieve and mixed thoroughly. The solution of
polyvinyl-pyrrolidone is mixed with the resultant powders, which
are then passed through a 16 mesh U.S. sieve. The granules so
produced are dried at 50.degree. to 60.degree. C. and passed
through a 16 mesh U.S. sieve. The sodium carboxymethyl starch,
magnesium stearate, and talc, previously passed through a No. 30
mesh U.S. sieve, are then added to the granules, which after
mixing, are compressed on a tablet machine to yield tablets each
weighing 150 mg.
Example 5
Formulation 5
Capsules, each containing 40 mg of medicament, are made as
follows:
TABLE-US-00007 Quantity Ingredient (mg/capsule) Active Ingredient
40.0 mg Starch 109.0 mg Magnesium stearate 1.0 mg Total 150.0
mg
The active ingredient, cellulose, starch, an magnesium stearate are
blended, passed through a No. 20 mesh U.S. sieve, and filled into
hard gelatin capsules in 150 mg quantities.
Example 6
Formulation 6
Suppositories, each containing 25 mg of active ingredient, are made
as follows:
TABLE-US-00008 Ingredient Amount Active Ingredient 25 mg Saturated
fatty acids glycerides to 2,000 mg
The active ingredient is passed through a No. 60 mesh U.S. sieve
and suspended in the saturated fatty acid glycerides previously
melted using the minimum heat necessary. The mixture is then poured
into a suppository mold of nominal 2.0 g capacity and allowed to
cool.
Example 7
Formulation 7
Suspensions, each containing 50 mg of medicament per 5.0 ml dose,
are made as follows:
TABLE-US-00009 Ingredient Amount Active Ingredient 50.0 mg Xanthan
gum 4.0 mg Sodium carboxymethyl cellose (11%) Microcrystalline
cellulose (89%) 500 mg Sucrose 1.75 g Sodium benzoate 10.0 mg
Flavor and color q.v. Purified water to 5.0 ml
The medicament, sucrose, and xanthan gum are blended, passed
through a NO.1 0 mesh U.S. sieve, and then mixed with a previously
made solution of the microcrystalline cellulose and sodium
carboxymethyl cellulose in water. The sodium benzoate, flavor, and
color are diluted with some of the water and added with stirring.
Sufficient water is then added to produce the required volume.
Example 8
Formulation 8
Hard gelatin tablets, each containing 15 mg of active ingredient,
are made as follows:
TABLE-US-00010 Quantity Ingredient (mg/capsule) Active Ingredient
15.0 mg Starch 407.0 mg Magnesium stearate 3.0 mg Total 425.0
mg
The active ingredient, cellulose, starch, and magnesium stearate
are blended, passed through a No. 20 mesh U.S. sieve, and filled
into hard gelatin capsules in 560 mg quantities.
Example 9
Formulation 9
An intravenous formulation may be prepared as follows:
TABLE-US-00011 Ingredient (mg/capsule) Active Ingredient 250.0 mg
Isotonic saline 1000 ml
Therapeutic compound compositions generally are placed into a
container having a sterile access port, for example, an intravenous
solution bag or vial having a stopper pierceable by a hypodermic
injection needle or similar sharp instrument.
Example 10
Formulation 10
A topical formulation may be prepared as follows:
TABLE-US-00012 Ingredient Quantity Active Ingredient 1-10 g
Emulsifying Wax 30 g Liquid Paraffin 20 g White Soft Paraffin to
100 g
The white soft paraffin is heated until molten. The liquid paraffin
and emulsifying wax are incorporated and stirred until dissolved.
The active ingredient is added and stirring is continued until
dispersed. The mixture is then cooled until solid.
Example 11
Formulation 11
An aerosol formulation may be prepared as follows: A solution of
the candidate compound in 0.5% sodium bicarbonate/saline (w/v) at a
concentration of 30.0 mg/mL is prepared using the following
procedure:
Preparation of 0.5% Sodium Bicarbonate/Saline Stock Solution: 100.0
mL
TABLE-US-00013 Ingredient Gram/100.0 mL Final Concentration Sodium
Bicarbonate 0.5 g 0.5% Saline q.s. ad 100.0 mL q.s. ad 100%
Procedure:
1. Add 0.5 g sodium bicarbonate into a 100 mL volumetric flask.
2. Add approximately 90.0 mL saline and sonicate until
dissolved.
3. Q.S. to 100.0 mL with saline and mix thoroughly.
Preparation of 30.0 mg/mL Candidate Compound: 10.0 mL
TABLE-US-00014 Ingredient Gram/100.0 mL Final Concentration
Candidate Compound 0.300 g 30.0 mg/mL .05% Sodium q.s. ad 10.0 mL
q.s. ad 100% Bicarbonte/Saline Stock Solution
Procedure:
1. Add 0.300 g of the candidate compound into a 10.0 mL volumetric
flask.
2. Add approximately 9.7 mL of 0.5% sodium bicarbonate/saline stock
solution.
3. Sonicate until the candidate compound is completely
dissolved.
4. Q.S. to 10.0 mL with 0.5% sodium bicarbonate/saline stock
solution and mix.
Example 12
Synthesis of
1-(4-ethoxyphenyl)-5-[(E)-2-(4-ethylphenyl)vinyl]benzimidazole
(Compound 1),
1-(4-ethoxyphenyl)-5-[(Z)-2-(4-ethylphenyl)vinyl]benzimidazole
(Compound 2), and
1-(4-ethoxyphenyl)-5-[2-(4-ethylphenyl)-ethyl]benzimidazole
(Compound 27)
1-(4-ethoxyphenyl)-5-[(E)-2-(4-ethylphenyl)-vinyl]benzimidazole
(Compound 1),
1-(4-ethoxyphenyl)-5-[(Z)-2-(4-ethylphenyl)vinyl]benzimidazole
(Compound 2), and
1-(4-ethoxyphenyl)-5-[2-(4-ethylphenyl)-ethyl]benzimidazole
(Compound 27) were synthesized according to the following
scheme:
##STR00073##
Example 12 was used as general procedure for compounds 1, 2, 4, 5,
6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 27 and 43
Synthesis of 4-Bromo-N-(4-ethoxyphenyl)-2-nitroaniline (compound
1-2)
To a solution of 4-bromo-1-fluoro-2-nitrobenzene (75.0 g, 0.341
mol, 1.0 equiv) in acetonitrile (375 mL) was added triethylamine
(55 mL, 0.394 mol, 1.15 equiv) and 4-ethoxyaniline (55 mL, 0.427
mol, 1.25 equiv). The resulting red solution was stirred at reflux
overnight and then cooled and concentrated under reduced pressure.
The residue was partitioned between ethyl acetate (2.5 L) and water
(1 L). The layers were separated and the aqueous layer was
back-extracted with ethyl acetate (200 mL). The combined organic
layers were dried over sodium sulfate and concentrated under
reduced pressure. The crude material was slurried in tert-butyl
methyl ether (250 mL) and filtered to give compound 1-2 (96.7 g,
84% yield) as a red solid which was used in the next step without
further purification.
Synthesis of 4-Bromo-N1-(4-ethoxyphenyl)benzene-1,2-diamine
(compound 1-3)
A solution of compound 1-2 (96.7 g, 0.287 mol, 1.0 equiv) in ethyl
acetate (2.5 L) was heated to 50.degree. C. Tin chloride dihydrate
(226.6 g, 1.00 mol, 3.5 equiv) was added in solid portions over 6
minutes. The temperature decreased from 51.5 to 48.5.degree. C.
during the addition and the color changed to orange. Heating was
continued until LC-MS indicated that no starting material remained.
The reaction was cooled to room temperature and aqueous sodium
bicarbonate was added until the pH was basic (3 L). This mixture
was stirred for 1 hour and filtered through Celite. The precipitate
was washed well with ethyl acetate and water. The filtrate was
transferred to a separatory funnel and the layers were separated.
The organic layer was dried over sodium sulfate and evaporated
under reduced pressure to give compound 1-3 (86.7 g, 98% yield) as
a brownish red powder, which was used in the next step without
further purification.
Synthesis of 5-Bromo-1-(4-ethoxyphenyl)-1H-benzo[d]imidazole
(compound 1-4)
To a solution of compound 1-3 (86.7 g, 0.28 mol, 1.0 equiv) in
ethanol (2.2 L) was added formamidine acetate (88.8 g, 0.85 mol, 3
equiv). The reaction was heated at reflux for 9 hours and cooled to
room temperature while stirred overnight. The solvent was removed
under reduced pressure and the residue was diluted with water (500
mL), stirred for 30 minutes and filtered. The resulting solid was
rinsed well with water and azeotroped repeatedly with toluene. The
solid was dried in a vacuum oven at 50.degree. C. to give compound
1-4 (83.5 g, 94% yield) as an orange solid which was used without
further purification.
Synthesis of 1-(4-Ethoxyphenyl)-1H-benzo[d]imidazole-5-carbonitrile
(compound 1-5)
A mixture of N,N-dimethylacetamide (125 mL), water (3 mL), and
poly(methoxyhydro)siloxane (3 mL) was degassed with a stream of
nitrogen for 15 minutes. Compound 1-4 (5 g, 15.7 mmol, 1 equiv.),
zinc cyanide (3.7 g, 31.5 mmol, 2 equiv.), and zinc dust (410 mg,
6.3 mmol, 0.4 equiv.) were added to the mixture which was heated to
100.degree. C.
Dichloro[1,1'-bis(diphenylphosphino)ferrocene]palladium (II)
dichloromethane adduct (255 mg, 0.3 mmol, 0.05 equiv.) was added
and heating was continued for 3 hours. The reaction was allowed to
cool to room temperature, poured into 500 mL of water and extracted
with ethyl acetate (2.times.500 mL). The combined organic layers
were dried over sodium sulfate and concentrated under reduced
pressure to give compound 1-5 as a light pink solid (3.6 g, 88%
yield).
Synthesis of 1-(4-Ethoxyphenyl)-1H-benzo[d]imidazole-5-carbaldehyde
(compound 1-6)
A solution of compound 1-5 (3.6 g, 13.5 mmol, 1 equiv.) in
dichloromethane (90 mL) was cooled with a dry ice/acetonitrile
bath. A 1.5 M solution of diisobutyl aluminumhydride in toluene,
(2.88 g, 13.5 mL, 20.2 mmol, 1.5 equiv.) was added drop wise via an
addition funnel. Upon completion of the addition, the reaction was
allowed to slowly warm to room temperature. The reaction was poured
into a 10% sodium potassium tartrate solution (250 mL) and stirred
for 20 minutes. The layers were separated and the dichloromethane
was washed with saturated brine (100 mL). The organic layer was
dried over sodium sulfate and concentrated under reduced pressure.
The residue was purified by flash chromatography eluting with a
gradient of 0-25% ethyl acetate in heptanes to give compound 1-6 as
a white solid (1.6 g, 44% yield).
Synthesis of (4-Ethylbenzyl)triphenylphosphonium chloride (compound
1-8)
To a stirred solution of 4-ethylbenzylchloride (1.54 g, 10 mmol, 1
equiv) was added triphenyl phosphine (2.62 g, 10 mmol, 1 equiv) in
toluene (30 mL). The reaction was heated at reflux for 48 hours and
allowed to cool to room temperature over the weekend. The
suspension was filtered, washed with toluene (2.times.5 mL) and
dried to give compound 1-8 as a white solid (2.5 g, 60% yield).
Synthesis of
1-(4-ethoxyphenyl)-5-[(E)-2-(4-ethylphenyl)vinyl]benzimidazole
(compound 1) and
1-(4-ethoxyphenyl)-5-[(Z)-2-(4-ethylphenyl)vinyl]benzimidazole
(compound 2)
Compound 1-8 (157 mg, 0.38 mmol, 1 equiv) was dissolved in
anhydrous tetrahydrofuran (5 mL) and cooled to -78.degree. C. A
2.5M solution of n-butyl lithium in hexanes (160 .mu.l, 0.40 mmol,
1.05 equiv) was added and the reaction was stirred at -78.degree.
C. for 1 hour. Compound 1-6 (100 mg, 0.38 mmol, 1 equiv) was added
and the reaction was allowed to warm to room temperature over 2
hours. The reaction was concentrated and the residue was dissolved
in dichloromethane (3 mL). This solution was filtered and purified
via chromatography utilizing an AnaLogix 4 g column eluting with a
gradient of 0-40% ethyl acetate in heptanes. This gave
1-(4-ethoxyphenyl)-5-(4-ethylstyryl)-1H-benzo[d]imidazole as a pale
yellow semisolid (85 mg, 61% yield). An additional run was made at
twice the scale and the cis and trans isomers were separated on an
AnaLogix 8 g column eluting with a gradient of 0-40% ethyl acetate
in heptanes to give 101 mg of compound 1 (37% yield) and 42 mg of
compound 2 (15% yield).
Synthesis of
1-(4-Ethoxyphenyl)-5-(4-ethylphenethyl)-1H-benzo[d]imidazole
(compound 27)
A mixture of compound 1 and compound 2 (75 mg, 0.20 mmol, 1 equiv)
was dissolved in methanol (40 mL) and 20% palladium on carbon (15
mg, 50% wet) was added. The reaction was hydrogenated at 60 psi for
18 hours. The reaction was filtered through Celite and the pad was
washed with methanol (2.times.10 mL). The filtrates were
concentrated under reduced pressure. The residue was concentrated
from heptanes (2.times.5 ml) to give compound 27 as a tan solid (68
mg, 88% yield).
Example 13
Synthesis of
E-1-(5-Ethoxypyridin-2-yl)-5-(4-ethylstyryl)-1H-benzo[d]imidazole
hydrochloride (compound 18) and
Z-1-(5-ethoxypyridin-2-yl)-5-(4-ethylstyryl)-1H-benzo[d]imidazole
hydrochloride (compound 19)
E-1-(5-Ethoxypyridin-2-yl)-5-(4-ethylstyryl)-1H-benzo[d]imidazole
hydrochloride (compound 18) and
Z-1-(5-ethoxypyridin-2-yl)-5-(4-ethylstyryl)-1H-benzo[d]imidazole
hydrochloride (compound 19) were synthesized according to the
following scheme:
##STR00074## ##STR00075##
Example 13 was used as general procedure for compounds 18, 19, 20,
21 and 42. The synthesis of compound 42 required an additional step
(Grignard reaction) following the installation of a methyl ester
group from the Wittig reaction.
Synthesis of N-(5-Ethoxypyridin-2-yl)pivalamide (compound 18-2)
Iodoethane (4.98 g, 2.55 mL, 31.90 mmol, 1.64 equiv) was added to a
suspension of N-(5-hydroxypyridin-2-yl)pivalamide (18-1) (3.76 g,
19.38 mmol, 1.0 equiv) and Cs.sub.2CO.sub.3 (10.37 g, 31.94 mmol,
1.64 equiv) in acetonitrile (125 mL) and the mixture was stirred
overnight. The reaction mixture was combined with that from a
smaller run (from 1 g of 18-1), filtered, and the solids were
washed with ethyl acetate (150 mL). The filtrate was concentrated
to near dryness and the residue was partitioned between ethyl
acetate (175 mL) and H.sub.2O (100 mL). The organic phase was
washed with saturated brine (100 mL), dried over sodium sulfate,
filtered, and concentrated under reduced pressure to give crude
compound 18-2 (4.59 g, 67% yield) as a tan solid that was used in
the next step.
Synthesis of 5-Ethoxypyridin-2-amine (compound 18-3)
A mixture of crude compound 18-2 (4.59 g, 20.67 mmol, 1.0 equiv)
and 3M HCl (75 mL) was refluxed with a Dean-Stark trap to collect
pivalic acid that was formed. After 2 hours, the mixture was cooled
to room temperature followed by an ice bath. The mixture was made
basic (pH 9) by the slow addition of 6N sodium hydroxide. The
mixture was extracted with ethyl acetate (1.times.100 mL,
1.times.50 mL). The combined organic layers were washed with
saturated brine, dried over sodium sulfate, filtered, and
concentrated under reduced pressure to give crude compound 18-3
(2.54 g, 86% yield) as a tan solid that was used in the next
step.
Synthesis of 4-(5-Ethoxypyridin-2-ylamino)-3-nitrobenzonitrile
(compound 18-4)
Triethylamine (2.04 g, 2.8 mL, 20.16 mmol, 1.15 equiv) was added to
a solution of crude compound 18-3 (2.54 g, 18.40 mmol, 1.05 equiv)
and 4-fluoro-3-nitrobenzonitrile (2.90 g, 17.53 mmol, 1.0 equiv) in
acetonitrile (70 mL). The yellow-orange solution was heated to
reflux. The mixture became red-orange that deepened to red. After 4
hours, the mixture was cooled to room temperature and concentrated
under reduced pressure. The residue was partitioned between ethyl
acetate (300 mL) and H.sub.2O (250 mL). Some insoluble red solid
was present at the interface. The organic phase was filtered to
remove the small amount of red solid (LC-MS showed the solid was
18-4). The filtrate was washed with H.sub.2O (20 mL), saturated
brine (100 mL), dried over sodium sulfate, filtered and
concentrated under reduced pressure. The residual solid was
combined with that from above, triturated with tert-butyl methyl
ether, filtered and dried to give compound 18-4 (2.20 g, 42% yield,
87% purity) as a red solid.
Synthesis of
3-Amino-4-(5-ethoxypyridin-2-ylamino)-3-nitrobenzonitrile (compound
18-5)
A red-brown solution of compound 18-4 (1.56 g, 5.5 mmol, 1.0 equiv)
in a mixture of ethyl acetate (100 mL) and tetrahydrofuran (25 mL)
was heated to 50.degree. C. and SnCl.sub.2-2H.sub.2O (4.35 g, 19.25
mmol, 3.5 equiv) was added in portions. The mixture was heated to
60-62.degree. C. and held for 3 hours. During the heating period,
the color of the reaction mixture gradually lightened to yellow and
a light suspension formed. The mixture was cooled to room
temperature, quenched by the slow addition of saturated sodium
bicarbonate (25 mL) and the resulting yellow suspension was stirred
for 15 min. The mixture was filtered through a pad of Celite and
the pad was washed with ethyl acetate (4.times.50 mL). The yellow
filtrate was washed with saturated sodium bicarbonate (100 mL) and
brine, dried over sodium sulfate and filtered. After concentration
under reduced pressure, 18-5 (1.37 g, 98% yield) was isolated as a
tan/brown solid that was used subsequently in the next step.
Synthesis of
1-(5-Ethoxypyridin-2-yl)-1H-benzo[d]imidazole-5-carbonitrile
(compound 18-6)
A dark-brown mixture of compound 18-5 (1.37 g, 5.39 mmol, 1.0
equiv), formamidine acetate (1.72 g, 16.5 mmol, 3.06 equiv) and
ethanol (70 mL) was refluxed for 17 hours. After 1.5 hours of
reflux, a light suspension had formed. The mixture was cooled to
room temperature and stirred over the weekend. The gray-brown
suspension was concentrated to near dryness under reduced pressure.
The residual thick slurry was diluted with H.sub.2O (75 mL) and the
suspension was triturated for 30 min with stirring. The suspension
was filtered and the solid was washed with water (2.times.50 mL)
and dried on the filter for 3.5 hours. After further drying in a
vacuum oven at 50.degree. C. overnight, compound 18-6 (1.31 g, 93%
yield) was obtained as a brown solid.
Synthesis of
1-(5-Ethoxypyridin-2-yl)-1H-benzo[d]imidazole-5-carbaldehyde
(compound 18-7)
Compound 18-6 (0.53 g, 2.0 mmol, 1.0 equiv) was dissolved in 98%
formic acid. Raney Nickel 2800 (0.66 g of very H.sub.2O wet) was
suspended in H.sub.2O (4 mL) and added to the formic acid solution.
The mixture was heated to reflux for 30 min. The mixture was cooled
to room temperature and filtered through a pad of Celite and the
pad was washed with 25% aqueous ethanol (2.times.25 mL). The
filtrate was concentrated to a small volume under reduced pressure
and diluted with H.sub.2O which caused a thick tan slurry to form.
The slurry was diluted with sufficient dichloromethane (75 mL) to
dissolve all solids. The biphasic mixture was made basic (pH>7)
by the slow addition of saturated sodium bicarbonate, while
stirring vigorously. An emulsion formed whose phases separated very
slowly. The organic phase was initially dried with solid sodium
chloride and the supernatant solution decanted and further dried
over sodium sulfate. The mixture was filtered and concentrated
under reduced pressure to give a tan/brown solid. The crude product
was purified on an AnaLogix automated chromatography system
(dry-loaded) eluting with a gradient of 0-5% methanol in
dichloromethane to give compound 18-7 (0.35 g, 66% yield) as a
pale, yellowish-tan solid.
Synthesis of
E-1-(5-Ethoxypyridin-2-yl)-5-(4-ethylstyryl)-1H-benzo[d]imidazole
hydrochloride (compound 18) and
Z-1-(5-ethoxypyridin-2-yl)-5-(4-ethylstyryl)-1H-benzo[d]imidazole
hydrochloride (compound 19)
A white suspension of compound 1-8 (1.09 g, 2.62 mmol, 2.0 equiv)
in tetrahydrofuran (40 mL) was cooled to -55.degree. C. and a 2.5 M
solution of n-BuLi in hexanes (0.97 mL, 2.43 mmol, 1.85 equiv) was
added drop-wise at -55 to -50.degree. C. The yellow-orange,
suspension was stirred 1 hour at this same temperature range. The
mixture was cooled to -75.degree. C. and compound 18-7 (0.35 g,
1.31 mmol, 1.0 equiv) was added, using tetrahydrofuran (5 mL) to
rinse the flask. The mixture was allowed to warm to room
temperature and stirred 17.5 hours. The tan, light suspension was
concentrated to a small volume under reduced pressure and the
residue was partitioned between dichloromethane (75 mL) and a
sodium bicarbonate solution (50 mL). The organic phase was washed
with saturated brine (50 mL), dried over sodium sulfate, filtered
and concentrated under reduced pressure to give a tan viscous oil.
The crude product was purified on an AnaLogix automated
chromatography system (dry-loaded) eluting with a gradient of 0-60%
ethyl acetate/heptanes. Fractions containing the free base of
compound 18 were concentrated to give partially purified material.
The white solid was repurified on an AnaLogix automated
chromatography system eluting with a gradient of 0-3% methanol in
dichloromethane to give a colorless film that began to crystallize.
The film was dissolved in minimum volume of tert-butyl methyl
ether, diluted with heptanes and the mixture slowly concentrated
under reduced pressure to give the free base of compound 19 (170
mg, 35% yield) as a white solid. A 4M HCl solution in dioxane (0.4
mL) was added drop-wise to a solution of the free base of compound
19 (140 mg) in dichloromethane (20 mL). The solution was stirred at
room temperature for 2 hours, diluted with toluene (10 mL) and the
mixture was concentrated under reduced pressure. The residual solid
was suspended in toluene (10 mL) and the suspension concentrated
under reduced pressure. The solid was triturated with heptanes (10
mL), filtered, washed with heptanes (10 mL) and dried under
nitrogen. The solid was further dried overnight in a vacuum oven at
40.degree. C. to give compound 19 (134 mg) as a slightly off-white
solid. Fractions containing the free base of compound 18 were
concentrated under reduced pressure to give partially purified
material. The viscous film was repurified on an AnaLogix automated
chromatography system eluting with a gradient of 0-3% methanol in
dichloromethane to give a colorless film that began to crystallize.
The partially crystallized residue was triturated with a minimum
volume of tert-butyl methyl ether and the suspension was diluted
with heptanes followed by concentration to give the free base of
compound 18 (190 mg, 44% yield) as a white solid. The HCl salt form
was prepared in an analogous fashion to 19 to give 164 mg of
compound 18 as a slightly off-white solid.
Example 14
Synthesis of
(Z)-3-(4-Ethoxyphenyl)-6-(4-ethylstyryl)-3H-imidazo[4,5-b]pyridine
(compound 22)
(Z)-3-(4-Ethoxyphenyl)-6-(4-ethylstyryl)-3H-imidazo[4,5-b]pyridine
(compound 22) was synthesized according to the following
scheme:
##STR00076## ##STR00077##
Example 14 was used as general procedure for compounds 22 and
24
Synthesis of 6-(4-Ethoxyphenylamino)-5-nitronicotinic acid
(compound 22-2)
To a solution of 6-chloro-5-nitronicotinic acid (22-1) (10 g, 49
mmol, 1.0 equiv) in acetonitrile (150 mL) was added triethylamine
(15.1 mL, 109 mmol, 2.2 equiv) and 4-ethoxyaniline (6.7 mL, 52
mmol, 1.05 equiv). The mixture was heated refluxed for 18 hours and
concentrated under reduced pressure. The residue was suspended in
water (100 mL) and the pH adjusted to 4 with 6N hydrochloric acid.
The aqueous phase was extracted with a 2:1 mixture of ethyl acetate
and tetrahydrofuran (4.times.100 mL). The organic layers were
combined, dried over sodium sulfate, and concentrated under reduced
pressure to give crude compound 22-2 (14 g, 96% yield) as a black
solid.
Synthesis of
3-(4-Ethoxyphenyl)-3H-imidazo[4,5-b]pyridine-6-carboxylic acid
(compound 22-4)
Crude compound 22-2 (14 g, 46.2 mmol, 1.0 equiv) was suspended in
methanol (250 mL) and 20% palladium on carbon (1.5 g, 50% wet) was
added. The reaction was hydrogenated @ 50 psi for 78 hours,
filtered through Celite and the pad was washed with methanol (50
mL). This solution was carried on to the next step without any
further workup. To this solution of 22-3 (.about.10 g, 33.6 mmol,
1.0 equiv) in methanol (225 ml) was added formamidine acetate (10
g, 96 mmol, 2.8 equiv). The reaction was refluxed for 18 hours. The
solvent was removed under reduced pressure and water (100 mL) was
added. The pH was adjusted to 4 with 6N hydrochloric acid. The
aqueous phase was extracted with a mixture of 2:1 ethyl acetate and
tetrahydrofuran (4.times.100 mL). The organic phases were combined,
dried over sodium sulfate, and concentrated under reduced pressure
to give compound 22-4 (8.3 g, .about.75% yield) as a brown solid
which was used in the next step without further purification.
Synthesis of Methyl
3-(4-ethoxyphenyl)-3H-imidazo[4,5-b]pyridine-6-carboxylate
(compound 22-5)
Compound 22-4 (3 g, 10.6 mmol, 1 equiv) was dissolved in methanol
(300 mL) and sulfuric acid (0.5 mL) was added. The reaction was
refluxed for 48 hours and then concentrated under reduced pressure
to a slurry. The material was purified by column chromatography
with 30% ethyl acetate in heptanes to give compound 22-5 (1.0 g,
32% yield) as a pale yellow oil.
Synthesis of
(3-(4-Ethoxyphenyl)-3H-imidazo[4,5-b]pyridin-6-yl)methanol
(compound 22-6)
Compound 22-5 (750 mg, 2.5 mmol, 1 equiv) was dissolved in
anhydrous tetrahydrofuran (20 mL) and a 1.0M super hydride solution
in tetrahydrofuran (6.3 mL, 6.3 mmol, 2.5 equiv) was added. The
reaction was stirred at room temperature for 1 hour and then poured
into saturated ammonium chloride (100 mL). The aqueous phase was
extracted with ethyl acetate (4.times.20 mL). The organic layers
were combined, dried over sodium sulfate, and concentrated under
reduced pressure. The brown residue was purified by column
chromatography with a gradient of 50-100% ethyl acetate in heptanes
with a final flush of ethanol to give 22-6 (600 mg, 70% yield) as a
pale yellow semi-solid.
Synthesis of
3-(4-Ethoxyphenyl)-3H-imidazo[4,5-b]pyridine-6-carbaldehyde
(compound 22-7)
Compound 22-6 (570 mg, 2.1 mmol, 1 equiv) was dissolved in
tetrahydrofuran (30 mL) and Dess-Martin periodinane (1 g, 2.35
mmol, 1.1 mmol) was added. The reaction was stirred at room
temperature for 1 hour and then poured into saturated sodium
bicarbonate. The aqueous phase was extracted with dichloromethane
(4.times.10 mL). The organic layers were combined, dried over
sodium sulfate, filtered, and concentrated under reduced pressure.
The residue was triturated with methyl tert-butyl ether (2.times.10
mL) to give compound 22-7 (500 mg, 80% yield) as an off white
solid.
Synthesis of
(Z)-3-(4-Ethoxyphenyl)-6-(4-ethylstyryl)-3H-imidazo[4,5-b]pyridine
(compound 22)
Compound 1-8 (328 mg, 0.78 mmol, 1.05 equiv) was dissolved in
anhydrous tetrahydrofuran (10 mL) and cooled to -78.degree. C. A
2.5 M solution of n-Butyl lithium in hexane (315 .mu.L, 0.78 mmol,
1.05 equiv) was added and the reaction was stirred at -78.degree.
C. for 1 hour. Then, compound 22-7 (200 mg, 0.75 mmol, 1 equiv) was
added and the reaction was allowed to warm to room temperature over
2 hours. The reaction was concentrated under reduced pressure and
the residue was dissolved in dichloromethane (3 mL). This solution
was filtered and chromatographed on an AnaLogix 8 g column eluting
with a gradient of 0-60% ethyl acetate in heptanes to give pure
compound 22 (35 mg, 13% yield). An additional run was carried out
to give a roughly equivalent amount of pure product.
Example 15
Synthesis of
(E)-3-(4-ethoxyphenyl)-6-(4-ethylstyryl)-3H-imidazo[4,5-b]pyridine
(compound 23)
(E)-3-(4-ethoxyphenyl)-6-(4-ethylstyryl)-3H-imidazo[4,5-b]pyridine
(compound 23) was synthesized according to the following
scheme:
##STR00078##
Example 15 was used as general procedure for compounds 3, 23 and
25
Compound 23-1 was prepared in a similar manner as compound 1-4
Synthesis of 1-Ethyl-4-vinylbenzene (compound 23-3)
Methyltriphenylphosphonium iodide (8.08 g, 20 mmol, 1 equiv) was
dissolved in anhydrous tetrahydrofuran (50 mL) and cooled to
-78.degree. C. A 2.5 M n-butyl lithium in hexane solution (8 mL, 20
mmol, 1 equiv) was added, the reaction was stirred at -78.degree.
C. for 1 hour and allowed to warm to room temperature over 1 hour.
4-Ethylbenzaldehyde (2.75 mL, 20 mmol, 1 equiv) was added as a
solution in tetrahydrofuran (15 mL) and the reaction was allowed to
stir at room temperature for 2 hours. The reaction was concentrated
under reduced pressure and the residue was suspended in heptanes
(60 mL). This suspension was filtered through basic alumina (20 g)
and the pad was washed with heptanes (50 mL). The solvent was
removed under reduced pressure to give compound 23-3 as a pale
yellow oil (2 g, 76% yield).
Synthesis of
(E)-3-(4-ethoxyphenyl)-6-(4-ethylstyryl)-3H-imidazo[4,5-b]pyridine
(compound 23)
Compound 23-1 (150 mg, 0.47 mmol, 1 equiv), compound 23-3 (187 mg,
1.42 mmol, 3 equiv) and triethylamine (1 mL) were dissolved in
anhydrous dimethyl formamide (2 mL). Palladium acetate (6.3 mg,
0.028 mmol, 0.06 equiv) and tri-o-tolyl phosphine (14 mg, 0.056
mmol, 0.1 equiv) were added and the reaction was heated in the
microwave at 150.degree. C. for 1.5 hours. The reaction was poured
into 1:1 mixture of water and ethyl acetate (20 mL), and the layers
were separated. The aqueous phase was extracted with ethyl acetate
(3.times.5 mL). The organic layers were combined and dried over
sodium sulfate. The solvent was removed under reduced pressure and
the resulting residue was chromatographed on an AnaLogix 8 g column
eluting with a gradient of 0-100% ethyl acetate in heptanes to give
compound 23 as an off white solid (96 mg, 55% yield).
Example 16
Synthesis of
3-(4-ethoxyphenyl)-6-[2-(4-ethylphenyl)-ethynyl]imidazo[4,5-b]pyridine
(compound 26) and
3-(4-Ethoxyphenyl)-6-(4-ethylphenethyl)-3H-imidazo[4,5-b]pyridine
(compound 28)
3-(4-ethoxyphenyl)-6-[2-(4-ethylphenyl)-ethynyl]imidazo[4,5-b]pyridine
(compound 26) and
3-(4-Ethoxyphenyl)-6-(4-ethylphenethyl)-3H-imidazo[4,5-b]pyridine
(compound 28) was synthesized according to the following
scheme:
##STR00079##
Example 16 was used as general procedure for compounds 26, 28 and
35.
Synthesis of
3-(4-Ethoxyphenyl)-6-((4-ethylphenyl)ethynyl)-3H-imidazo[4,5-b]pyridine
(26)
Compound 23-1 (250 mg, 0.8 mmol, 1 equiv), 4-ethylphenyl acetylene
(132 .mu.L, 0.95 mmol, 1.2 equiv) and triethyl amine (200 .mu.L,
2.7 mmol, 1.8 equiv) were suspended in toluene (6 mL).
Bis(triphenylphosphine) palladium dichloride (27 mg, 0.07 mmol,
0.05 equiv) and copper (I) iodide (7 mg, 0.07 mmol, 0.05 equiv)
were added and the reaction was stirred at room temperature for 4
hours. The reaction was filtered through silica gel (2 g) and the
silica gel washed with toluene (2.times.5 mL). The filtrate was
concentrated under reduced pressure to give an orange semi-solid.
Two runs were combined and chromatographed on an AnaLogix (24 g)
column eluting with a gradient of 0-100% ethyl acetate in heptanes
to give compound 26 as an orange solid (150 mg, 34% yield).
Synthesis of
3-(4-Ethoxyphenyl)-6-(4-ethylphenethyl)-3H-imidazo[4,5-b]pyridine
(compound 28)
Compound 26 (100 mg, 0.27 mmol, 1 equiv) was dissolved in methanol
and 20% palladium on carbon (10 mg, 50% wet) was added. The
reaction was hydrogenated at 60 psi for 96 hours. During this time,
additional catalyst (5 mg) was added on two occasions to complete
the reduction. When the reaction was shown to be complete, it was
filtered through Celite and the pad was washed with methanol (10
mL). The solution was concentrated and the residue was triturated
with heptanes (3.times.1 mL) to give compound 28 as a tan solid (54
mg, 52% yield).
Example 17
Synthesis of
1-(4-Ethoxyphenyl)-5-(4-ethylbenzyloxy)-1H-benzo[d]imidazole
(compound 29)
1-(4-Ethoxyphenyl)-5-(4-ethylbenzyloxy)-1H-benzo[d]imidazole
(compound 29) was synthesized according to the following
scheme:
##STR00080##
Example 17 was used as general procedure for compounds 29, 31 and
32.
Synthesis of 1-(4-Ethoxyphenyl)-1H-benzo[d]imidazol-5-ol (compound
29-1)
Compound 1-4 (0.3 g, 0.9 mmol, 1.0 equiv) was dissolved in dioxane
(150 mL) and then bis(pinacolato)diboron (0.3 g, 1.1 mmol, 1.2
equiv), potassium acetate (0.2 g, 1.9 mmol, 2.0 equiv), and
[1,1'-bis(diphenylphosphino)ferrocene]-palladium dichloride complex
with dichloromethane (40 mg, 0.05 mmol, 0.05 equiv) were added in
succession. The reaction was degassed under a stream of nitrogen
for 10 minutes and refluxed overnight. The reaction was filtered
through Celite and which was then washed with ethyl acetate (50
mL). The solvent was evaporated under reduced pressure and the
residue was dissolved in tetrahydrofuran (20 mL). The solution was
cooled to 0.degree. C. and glacial acetic acid (90 .mu.L, 1.4 mmol,
1.5 equiv) was added dropwise. The mixture was stirred at 0.degree.
C. for 1 h, at which time an aqueous solution of hydrogen peroxide
(30% wt. in water, 220 .mu.L, 1.9 mmol, 2 equiv) was added slowly.
The reaction mixture was stirred for 5 h, at which time LC-MS
showed the reaction was completed and the mixture was diluted with
water. The aqueous phase was discarded and the organic layer was
treated with an aqueous solution of sodium sulfite (0.2 g, 1.9
mmol, 2 equiv) and stirred at room temperature for 15 minutes. The
organic phase was separated and dried over sodium sulfate. The
solvent was evaporated under reduced pressure to give compound 29-1
as a red solid (0.3 g, quantitative yield) which was used in the
next step without further purification.
Synthesis of
1-(4-Ethoxyphenyl)-5-(4-ethylbenzyloxy)-1H-benzo[d]imidazole
(compound 29)
To a solution of triphenylphosphine (0.5 g, 2.0 mmol, 2.0 equiv) in
tetrahydrofuran (10 mL) at 0.degree. C. was added
diisopropyldiazocarboxylate (0.4 mL, 2.0 mmol, 2.0 equiv) dropwise.
The mixture was stirred at 0.degree. C. for 50 minutes. At this
time, a solution of compound 29-1 (0.3 mL, 1.0 mmol, 1.0 equiv) and
4-ethylbenzyl alcohol (0.2 mL, 1.1 mmol, 1.1 equiv) in
tetrahydrofuran (10 mL) was added slowly. The reaction was stirred
at room temperature overnight at which time LC-MS indicated the
reaction was complete. The mixture was concentrated under reduced
pressure and absorbed on silica gel (3 g). The compound was
purified on an AnaLogix (SF 15-24 g) column eluting with a gradient
of from 10-60% ethyl acetate in heptanes for 30 minutes followed by
100% ethyl acetate for 5 minutes to give compound 29 as a tan solid
(77 mg, 21% yield).
Example 18
Synthesis of
5-(4-Isopropylbenzyloxy)-1-(4-methoxyphenyl)-1H-benzo[d]imidazole
(compound 30)
5-(4-Isopropylbenzyloxy)-1-(4-methoxyphenyl)-1H-benzo[d]imidazole
(compound 30) was synthesized according to the following
scheme:
##STR00081##
Synthesis of 4-(4-Methoxyphenylamino)-3-nitrophenol (compound
30-2)
To a solution of 4-fluoro-3-nitrophenol (2.0 g, 13 mmol, 1.0 equiv)
in N-methyl-2-pyrrolidone (10 ml) was added
N,N-diisopropylethylamine (2.2 mL, 13 mmol, 1.0 equiv) and
4-methoxyaniline (1.9 g, 15 mmol, 1.2 equiv). The mixture was
heated to 165.degree. C. overnight, at which time LC-MS indicated
that the reaction was complete. The mixture was cooled to room
temperature and diluted with ethyl acetate. The organic phase was
washed with water, saturated brine, dried over sodium sulfate and
evaporated under reduced pressure. The compound was purified on an
AnaLogix (SF 40-150 g) column using a gradient of 0-50% ethyl
acetate in heptanes over 45 minutes to give compound 30-2 as a red
solid (2.2 g, 67% yield).
Synthesis of 3-Amino-4-(4-methoxyphenylamino)phenol (compound
30-3)
Compound 30-2 (2.2 g, 8.5 mmol, 1.0 equiv) was dissolved in ethyl
acetate (200 mL) and 10% Pd/C (0.44 g, 50% wet with water) was
added. The reaction was hydrogenated at 20 psi for 4 h until
hydrogen consumption was complete. The material was filtered
through Celite and the pad was washed with ethyl acetate (200 mL).
The filtrate was concentrated under reduced pressure to give
compound 30-3 as a dark red oil (2.0 g, quantitative yield).
Synthesis of 1-(4-Methoxyphenyl)-1H-benzo[d]imidazol-5-ol (compound
30-4)
Compound 30-3 (1.0 g, 4.3 mmol, 1.0 equiv) was suspended in 4 N
aqueous hydrochloric acid (10 mL) and formic acid (1.3 mL) was
added. The reaction was heated in a sealed tube at 100.degree. C.
for 2 h, at which time LC-MS indicated the reaction was complete.
The reaction was cooled to room temperature and diluted with water
(30 mL). The pH of the mixture was adjusted to 8 with solid sodium
bicarbonate and extracted with ethyl acetate (3.times.50 mL). The
organic layers were combined, dried over sodium sulfate, and
evaporated under reduce pressure. The crude solid was triturated
with methyl tert-butyl ether to give compound 30-4 as a dark red
solid (0.9 g, 87% yield).
Synthesis of
5-(4-Isopropylbenzyloxy)-1-(4-methoxyphenyl)-1H-benzo[d]imidazole
(compound 30)
This procedure is analogous to the one used for the conversion of
compound 29-1 to compound 29. The compound was purified on an
AnaLogix (SF 25-40 g) column using a gradient of 0-70% ethyl
acetate in heptanes over 35 minutes to give compound 30 as a tan
solid (0.2 g, 28% yield).
Example 19
Synthesis of
1-(4-Ethoxyphenyl)-5-(4-ethylbenzylthio)-1H-benzo[d]imidazole
(compound 33)
1-(4-Ethoxyphenyl)-5-(4-ethylbenzylthio)-1H-benzo[d]imidazole
(compound 33) was synthesized according to the following
scheme:
##STR00082##
Synthesis of O-1-(4-Ethoxyphenyl)-1H-benzo[d]imidazol-5-yl
diethylcarbamothioate (compound 33-1)
A solution of compound 30-4 (0.4 g, 1.6 mmol, 1.0 equiv) in
tetrahydrofuran/dimethylformamide (1:1, 10 mL) was added dropwise
to a suspension of sodium hydride (60% dispersion in mineral oil)
(77 mg, 1.9 mmol, 1.2 equiv) in tetrahydrofuran (5 mL). After 10
minutes, diethylthiocarbamoyl chloride (0.3 g, 1.8 mmol, 1.1 equiv)
was added and the reaction heated at 60.degree. C. for 5 h. The
cooled mixture was poured in 1N aqueous sodium hydroxide (20 mL)
and extracted with ethyl acetate (3.times.20 mL). The organic
layers were combined, dried with sodium sulfate and evaporated
under reduced pressure. The compound was purified on an AnaLogix
(SF 15-24 g) column eluting with a gradient of 30-100% ethyl
acetate in heptanes over 40 minutes to give compound 33-1 as a
brown oil (0.4 g, 65% yield).
Synthesis of S-1-(4-Ethoxyphenyl)-1H-benzo[d]imidazol-5-yl
diethylcarbamothioate (compound 33-2)
A solution of compound 33-1 (0.5 g, 1.5 mmol, 1.0 equiv) in
N-methyl-2-pyrrolidone (4 ml) was placed in the microwave (250 W)
and heated at 250.degree. C. for 1.5 h, at which time TLC indicated
the reaction was complete. The mixture was cooled to room
temperature and diluted with ethyl acetate (20 mL). The organic
phase was washed with water (2.times.20 mL), dried over sodium
sulfate and evaporated under reduced pressure. The compound was
purified on an AnaLogix (SF 15-24 g) column eluting with a gradient
of 0-60% ethyl acetate in heptanes to give compound 33-2 as a brown
oil (0.13 g, 23% yield).
Synthesis of
1-(4-Ethoxyphenyl)-5-(4-ethylbenzylthio)-1H-benzo[d]imidazole
(compound 33)
A solution of compound 33-2 (0.13 g, 0.35 mmol, 1.0 equiv) in
ethanol (10 mL) was treated with 6 N aqueous potassium hydroxide (5
mL). The reaction was heated at reflux overnight, at which time
LC-MS indicated the reaction was complete (Note: the m/z observed
on the LC-MS corresponded to
1,2-bis(1-(4-ethoxyphenyl)-1H-benzo[d]imidazol-5-yl)disulfane). The
solvents were evaporated under reduced pressure, and the residue
was dissolved in ethanol (20 mL). The mixture was treated with
excess sodium borohydride (200 mg) and stirred at room temperature
until no more disulfide product was observed via LC-MS.
4-Ethylbenzyl chloride (61 mg, 0.39 mmol, 1.1 equiv) was added and
the mixture was stirred at room temperature overnight. The solvent
was evaporated under reduced pressure and the residue was diluted
with ethyl acetate. The organic layer was washed with saturated
aqueous sodium bicarbonate, dried over sodium sulfate, and
evaporated under reduce pressure. The compound was purified on an
AnaLogix (SF 10-8 g) column eluting with a gradient of 0-35% ethyl
acetate in heptanes over 25 minutes to give compound 33 as an off
white solid (50 mg, 10% yield).
Example 20
Synthesis of
N-((1-(4-Ethoxyphenyl)-1H-benzo[d]imidazol-5-yl)methyl)-4-ethylaniline
(compound 34)
N-((1-(4-Ethoxyphenyl)-1H-benzo[d]imidazol-5-yl)methyl)-4-ethylaniline
(compound 34) was synthesized according to the following
scheme:
##STR00083##
Synthesis of
N-((1-(4-Ethoxyphenyl)-1H-benzo[d]imidazol-5-yl)methyl)-4-ethylaniline
(compound 34)
To a solution of compound 1-6 (1 g, 3.8 mmol, 1 equiv.) in 30 mL of
methanol was added 4-ethylaniline (455 mg, 3.8 mmol, 1 equiv.) via
an addition funnel. Upon completion of the addition, the reaction
was heated to 60.degree. C. for 1 h and then allowed to cool to
room temperature. Upon reaching room temperature, sodium
borohydride (143 mg, 3.8 mmol, 1 equiv.) was added slowly and
stirred at room temperature for 30 minutes. A saturated solution of
sodium bicarbonate (10 mL) was added followed by stirring for 20
minutes. The reaction was diluted with dichloromethane (50 mL), the
organic layer was separated, dried over sodium sulfate and
concentrated under reduced pressure. The resulting material was dry
loaded onto an AnaLogix (80 g) column and eluted with a gradient of
25-100% ethyl acetate in heptanes to give compound 34 as a white
solid (430 mg, 31% yield).
Example 21
Synthesis of
5-[2-(4-tert-butylphenyl)-cyclopropyl]-1-(4-isopropoxyphenyl)-benzimidazo-
le (compound 36)
5-[2-(4-tert-butylphenyl)cyclopropyl]-1-(4-isopropoxyphenyl)-benzimidazol-
e (compound 36) was synthesized according to the following
scheme:
##STR00084## ##STR00085##
Synthesis of 1-(tert-Butyl)-4-(2,2-dibromocyclopropyl)-benzene
(Compound 36-2)
A solution of 1-(tert-butyl)-4-vinylbenzene (36-1) (29.1 g, 182
mmol, 1 equiv) and benzyltriethylammonium bromide (1.2 g, 4.4 mmol,
0.02 equiv) in bromoform (135 mL, 1.55 mol, 8.5 equiv) was cooled
to 0.degree. C. With vigorous mechanical stirring, a 50% aqueous
sodium hydroxide (145 mL, 2.77 mol, 23 equiv) was added in one
portion (caution: exothermic; temperature reached 60.degree. C.)
resulting in the formation of a thick tan suspension. Stirring was
continued for 2 hours while the reaction returned to room
temperature at which point GC-MS indicated the reaction was
complete. The reaction mixture was diluted with methyl tert-butyl
ether (200 mL) and filtered. The filtrate was transferred to a
separatory funnel and the layers were separated. The aqueous layer
was extracted with methyl tert-butyl ether (2.times.200 mL). The
combined organic layers were washed with saturated brine (500 mL),
dried over sodium sulfate, filtered, and evaporated under reduced
pressure to a brown liquid (90 g). The crude material was passed
through a plug of silica gel (300 g) eluting with heptanes to give
36-2 (67 g, quantitative yield) as a slightly yellow liquid.
Synthesis of (trans)-1-(2-Bromocyclopropyl)-4-(tert-butyl)benzene
(36-3)
A 2.5M solution of n-butyl lithium in hexane (22 mL, 55 mmol, 1.1
equiv) was added at such a rate keeping the temperature below
-70.degree. C. to a solution of 36-2 (16.6 g, 50 mmol, 1 equiv) in
tetrahydrofuran (250 mL). Upon completion of the addition, the
reaction was stirred for 2 hours at -78.degree. C. GC-MS of a
reaction aliquot quenched into methanol indicated 10% stating
material remained along with a 1:1 mixture of trans and cis
isomers. Additional 2.5 M n-butyl lithium in hexane (2 mL) was
added and the reaction was stirred an additional 1 hour at
-78.degree. C. The reaction was quenched at -78.degree. C. by the
addition of acetic acid (3 mL) in tetrahydrofuran (30 mL). The
mixture was warmed to room temperature, diluted with methyl
tert-butyl ether (300 mL) and extracted with 1 N HCl (300 mL). The
organic layer was washed with saturated brine (300 mL), dried over
sodium sulfate, filtered, and evaporated under reduced pressure.
The crude material was purified on an AnaLogix automated
chromatography system eluting with heptanes. The desired trans
isomer eluted first followed immediately by the cis isomer with
several mixed fractions in between. After evaporation, 36-3 was
recovered as a colorless liquid (3.3 g, 26% yield). The cis isomer
was also recovered (2.9 g, 23% yield). Note: The determination of
the relative stereochemistry (cis vs. trans) was done by comparing
coupling constants of the cyclopropane ring protons
(J.sub.cis>J.sub.trans).
Synthesis of
2-((trans)-2-(4-(tert-Butyl)phenyl)-cyclopropyl)-4,4,5,5-tetramethyl-1,3,-
2-dioxaborolane (36-4)
A 2.5M solution of n-butyl lithium in hexane (5 mL, 12.4 mmol, 1.5
equiv) was added to a solution of 36-3 (2.1 g, 8.2 mmol, 1 equiv)
in tetrahydrofuran (100 mL) at -78.degree. C. The mixture was
stirred at -78.degree. C. for 1 hour. Once completion of the
lithium/halogen exchange was confirmed by GC-MS of a reaction
aliquot quenched into methanol,
2-isopropoxy-4,4,5,5-tetramethyl-1,3,2-dioxaborolane (2.6 mL, 12.4
mmol, 1.5 equiv) was added in one portion (caution: exothermic;
temperature reached -50.degree. C.). Stirring was continued for 2
hours while warming to room temperature. The reaction was quenched
by the addition of saturated ammonium chloride (200 mL) and
extracted with methyl tert-butyl ether (250 mL). The organic layer
was washed with saturated brine (150 mL), dried over sodium
sulfate, filtered, and evaporated under reduced pressure to give
36-4 [3.2 g, quantitative yield, 85% purity (major impurity is
pinacol)] which forms a white semi-solid upon storage at
-20.degree. C.
Synthesis of 5-Bromo-1-(4-isopropoxyphenyl)-1H-benzo[d]imidazole
(36-7)
Compound 36-7 was prepared from compound 1-1 in a similar fashion
to that used to synthesize compound 1-4.
Synthesis of
5-((trans)-2-(4-(tert-Butyl)phenyl)-cyclopropyl)-1-(4-isopropoxyphenyl)-1-
H-benzo[d]imidazole (36)
A 100 mL round bottom flask was charged with 36-4 (1.5 g, 5 mmol,
1.5 equiv), 36-7 (1.1 g, 3.3 mmol, 1 equiv), tripotassium phosphate
dihydrate (3.46 g, 15 mmol, 4.5 equiv), tricyclohexyl phosphine
(280 mg, 1.0 mmol, 0.33 equiv), toluene (20 mL), and water (2 mL).
The mixture was degassed with a stream of nitrogen for 10 minutes.
Palladium (II) acetate (113 mg, 0.5 mmol. 0.15 equiv) was added and
the reaction was degassed with a stream of nitrogen for an
additional 5 minutes. The reaction was refluxed for 24 hours,
cooled to room temperature and filtered through a pad of Celite,
washing with methyl tert-butyl ether. The filtrate was transferred
to a separatory funnel and washed with water (100 mL), saturated
brine (100 mL), dried over sodium sulfate, filtered, and evaporated
under reduced pressure. The crude material was purified on an
AnaLogix automated chromatography system eluting with a gradient of
0-3% methanol in dichloromethane which removed baseline impurities.
The material was further purified on an AnaLogix automated
chromatography system eluting with a gradient of 0-15% acetone in
toluene to give 36 (370 mg, 27% yield) as a yellow glass.
Example 22
Synthesis of methyl
4-[(Z)-2-[1-(4-isopropoxyphenyl)-benzimidazol-5-yl]vinyl]benzoate
(compound 37),
2-[4-[(Z)-2-[1-(4-isopropoxyphenyl)-benzimidazol-5-yl]vinyl]phenyl]-propa-
n-2-ol (compound 38), and
5-[(Z)-2-[4-(1-fluoro-1-methyl-ethyl)phenyl]vinyl]-1-(4-isopropoxy-phenyl-
)benzimidazole (compound 39)
Methyl
4-[(Z)-2-[1-(4-isopropoxyphenyl)-benzimidazol-5-yl]vinyl]benzoate
(compound 37),
2-[4-[(Z)-2-[1-(4-isopropoxyphenyl)benzimidazol-5-yl]vinyl]phenyl]-propan-
-2-ol (compound 38), and
5-[(Z)-2-[4-(1-fluoro-1-methyl-ethyl)phenyl]-vinyl]-1-(4-isopropoxy-pheny-
l)benzimidazole (compound 39) were synthesized according to the
following scheme:
##STR00086##
Note that compound 41 was formed as a by-product during the Wittig
reaction to form compound 38. Compound 45 was isolated following
saponification of compound 37. Additionally, compound 61 was
synthesized in a similar fashion as compound 38.
Synthesis of
1-(4-Isopropoxyphenyl)-1H-benzo[d]imidazole-5-carbaldehyde
(39-2)
A suspension of Raney Nickel (6 g) in water (35 mL) was added to a
stirred solution of compound 39-1 (4.9 g, 18 mmol, 1.0 equiv) in
formic acid (35 mL). The reaction was refluxed for 2 hours, at
which point LC-MS analysis indicated the reaction was complete. The
mixture was cooled to room temperature, diluted with
dichloromethane (100 mL) and water (100 mL) and filtered through
Celite. The layers were separated and the aqueous portion was
extracted with dichloromethane (2.times.50 mL). The combined
organic layers were dried over sodium sulfate, filtered, and
evaporated under reduced pressure. The residue was purified on an
AnaLogix (SF 40-115 g) column eluting with a gradient of 0-3.5%
methanol in dichloromethane to give compound 39-2 as a white solid
(3.5 g, 72% yield).
Synthesis of (4-(Methoxycarbonyl)benzyl)triphenyl-phosphonium
bromide (39-4)
Compound 39-4 was prepared from compound 39-3 using a similar
procedure to that used to synthesize compound 1-8.
Synthesis of (Z)-Methyl
4-(2-(1-(4-isopropoxyphenyl)-1H-benzo[d]imidazol-5-yl)vinyl)benzoate
(37)
Compound 39-4 (5.9 g, 12 mmol, 1.0 equiv) was suspended in
anhydrous tetrahydrofuran (200 mL) and cooled to -78.degree. C. A
2.5 M solution of n-butyl lithium in hexane (5 mL, 13 mmol, 1.05
equiv) was added and the reaction was stirred at -78.degree. C. for
1 hour. Compound 39-2 (3.4 g, 12 mmol, 1.0 equiv) was added and the
reaction was allowed to warm to room temperature. After 12 hours,
LC-MS indicated the reaction was 80% completed. The reaction was
concentrated to dryness under reduced pressure. The residue was
purified on an AnaLogix (SF 40-150 g) column eluting with a
gradient of 0-100% ethyl acetate in heptanes to give compound 37
(2.6 g, 49% yield) as a light yellow oil.
Synthesis of
(Z)-2-(4-(2-(1-(4-Isopropoxyphenyl)-1H-benzo[d]imidazol-5-yl)vinyl)phenyl-
)propan-2-ol (38)
A 3.0M solution of methylmagnesium bromide in tetrahydrofuran (6.1
mL, 18 mmol, 3.0 equiv) was added at room temperature to a solution
of compound 37 (2.5 g, 6.1 mmol, 1.0 equiv) in anhydrous
tetrahydrofuran (100 mL). After 3 hours, LC-MS indicated the
reaction was completed. The reaction was quenched with an ice cold
saturated ammonium chloride. The layers were separated and the
aqueous portion was extracted with ethyl acetate (2.times.100 mL).
The combined organic layers were dried over sodium sulfate,
filtered, and evaporated under reduced pressure. The residue was
purified on an AnaLogix (SF 40-115 g) column eluting with a
gradient of 0-3.5% methanol in dichloromethane to give compound 38
as an light yellow oil (1.7 g, 68% yield).
Synthesis of
(Z)-5-(4-(2-Fluoropropan-2-yl)styryl)-1-(4-isopropoxyphenyl)-1H-benzo[d]i-
midazole (39)
Diethylaminosulfur trifluoride (0.18 mL, 1.3 mmol, 1.3 equiv) was
added to a solution of compound 38 (0.4 g, 0.97 mmol, 1.0 equiv) in
dichloromethane (50 mL) at 0.degree. C. The reaction was allowed to
warm to room temperature and after 3 hours LC-MS indicated the
reaction was complete. The reaction was quenched with water and
diluted with dichloromethane. The layers were separated and the
aqueous portion was extracted with dichloromethane (2.times.50 mL).
The combined organic layers were dried over sodium sulfate,
filtered, and evaporated under reduced pressure. The residue was
purified by preparative HPLC using a gradient of 0%-95% water (0.1%
formic acid) in acetonitrile (0.1% formic acid) to give compound 39
(120 mg) as a light yellow oil.
Example 23
Synthesis of
5-[(Z)-2-(4-isopropenylphenyl)-vinyl]-1-(4-isopropoxyphenyl)-benzimidazol-
e (compound 40)
5-[(Z)-2-(4-isopropenylphenyl)-vinyl]-1-(4-isopropoxyphenyl)-benzimidazol-
e (compound 40) was synthesized according to the following
scheme:
##STR00087## ##STR00088##
Synthesis of 1-(1-fluoro-1-methyl-ethyl)-4-methyl-benzene
(40-2)
Compound 40-2 was synthesized from compound 40-1 through a Grinard
reaction with methylmagnesium bromide using a procedure similar to
that used to prepare compound 39.
Synthesis of 1-(bromomethyl)-4-(1-fluoro-1-methyl-ethyl)benzene
(40-3)
A solution of 40-2 (0.5 g, 3.3 mmol, 1 equiv), N-bromosuccinimide
(0.58 g, 3.3 mmol, 1 equiv), and benzoyl peroxide (16 mg, 0.06
mmol, 2 mol %) in carbontetrachloride (10 mL) was heated under
reflux for 3 hours. The mixture was cooled, filtered and the
filtrate was concentrated under reduced pressure. Ethyl acetate (20
mL) and water (20 mL) were added and the layers were separated. The
organic portion was dried with sodium sulfate, filtered and
concentrated under reduced pressure to afford compound 40-3 (0.3 g,
45% yield).
Synthesis of
[4-(1-fluoro-1-methyl-ethyl)phenyl]methyl-triphenyl-phosphonium
bromide (40-5)
Compound 40-5 was prepared by reacting compound 40-3 with
diethylaminosulfur trifluoride using a procedure similar to that
used for compound 37 followed by treatment with triphenylphosphine
similar to the procedure utilized to synthesize compound 1-8.
Synthesis of
5-[(Z)-2-(4-isopropenylphenyl)-vinyl]-1-(4-isopropoxyphenyl)-benzimidazol-
e (40)
Compound 40 was the major product following a Wittig reaction that
followed a similar procedure to that used to prepare compound
38.
Example 24
Synthesis of
1,1,1-trifluoro-2-[4-[(Z)-2-[1-(4-isopropoxyphenyl)benzimidazol-5-yl]viny-
l]phenyl]propan-2-ol (compound 46)
1,1,1-trifluoro-2-[4-[(Z)-2-[1-(4-isopropoxyphenyl)benzimidazol-5-yl]viny-
l]phenyl]propan-2-ol (compound 46) was synthesized according to the
following scheme:
##STR00089##
Example 24 was used as a general procedure for the synthesis of
compounds 50, 51, 52, 53, 55, 56, 57, 58 and 59. Please note that
compounds 55 and 58 required an extra step following the Grignard
reaction involving either saponification (compound 55) or removal
of a Boc group (compound 58).
Synthesis of (4-iodobenzyl)triphenylphosphonium bromide (46-2)
Compound 46-2 was prepared from compound 46-1 using a similar
procedure to that used to synthesize compound 1-8.
Synthesis of
(Z)-5-(4-iodostyryl)-1-(4-isopropoxyphenyl)-1H-benzo[d]imidazole
(compound 46-3)
Compound 46-3 was synthesized in the same fashion as compound
1-8.
Synthesis of
1,1,1-trifluoro-2-[4-[(Z)-2-[1-(4-isopropoxyphenyl)benzimidazol-5-yl]viny-
l]phenyl]propan-2-ol (compound 46)
2M Isopropylmagnesium chloride in THF (3.85 mL, 7.75 mmol, 6.2
equiv) was added dropwise to a cold solution (-40.degree. C.) of
compound 46-3 (0.60 g, 1.25 mmol, 1 equiv) in anhydrous THF (12
mL). The reaction was stirred at -40.degree. C. for 30 minutes,
then cooled to -78.degree. C. 1,1,1-Trifluoroacetone (0.23 mL, 2.5
mmol, 2 equiv) was added dropwise and the reaction was stirred at
room temperature for 16 hours. The reaction was cooled to 0.degree.
C. and quenched with water (50 mL). The mixture was extracted with
ethyl acetate (3.times.50 mL) and the combined organic layers were
dried over sodium sulfate, filtered and concentrated under reduced
pressure. The residue was purified on an AnaLogix automated
chromatography system, eluting with a gradient of 0 to 40% ethyl
acetate in heptanes to give compound 46 as a white solid (0.14 g,
24% yield).
Example 25
Synthesis of
1,1,1,3,3,3-hexafluoro-2-[4-[(Z)-2-[1-(4-isopropoxyphenyl)benzimidazol-5--
yl]vinyl]phenyl]propan-2-ol (compound 47)
1,1,1,3,3,3-hexafluoro-2-[4-[(Z)-2-[1-(4-isopropoxyphenyl)benzimidazol-5--
yl]vinyl]phenyl]propan-2-ol (compound 47) was synthesized according
to the following scheme:
##STR00090##
Synthesis of
1,1,1,3,3,3-hexafluoro-2-[4-[(Z)-2-[1-(4-isopropoxyphenyl)benzimidazol-5--
yl]vinyl]phenyl]propan-2-ol (compound 47)
Cesium fluoride (0.23 g, 1.5 mmol, 0.9 equiv) and
(trifluoromethyl)trimethylsilane (0.75 mL, 5.1 mmol, 3 equiv) were
added to a cold solution (0.degree. C.) of compound 37 (0.7 g, 1.7
mmol, 1.0 equiv) in tetrahydrofuran (50 mL). The reaction was
stirred overnight at room temperature, when LC/MS analysis
indicated that the starting material was not completely consumed.
Additional (trifluoromethyl)trimethlysilane (0.38 mL, 2.6 mmol, 1.5
equiv) was added and after 6 hours the reaction was partitioned
between ethyl acetate (10 mL) and water (10 mL). The aqueous layer
was extracted with ethyl acetate (2.times.10 mL). The combined
organic layers were dried over sodium sulfate and concentrated
under reduced pressure. The residue was purified on an AnaLogix (SF
15-24 g) column, eluting with a gradient of 0 to 3% methanol in
dichloromethane, to give compound 47 as an off white solid (82 mg,
10% yield).
Example 26
Synthesis of
1-[4-[(Z)-2-[1-(4-isopropoxyphenyl)benzimidazol-5-yl]vinyl]phenyl]cyclopr-
opanol (compound 48)
1-[4-[(Z)-2-[1-(4-isopropoxyphenyl)benzimidazol-5-yl]vinyl]phenyl]cyclopr-
opanol (compound 48) was synthesized according to the following
scheme:
##STR00091##
Synthesis of
1-[4-[(Z)-2-[1-(4-isopropoxyphenyl)benzimidazol-5-yl]vinyl]phenyl]cyclopr-
opanol (compound 48)
2.7M Ethylmagnesium chloride (2.5 mL, 6.8 mmol, 2.8 equiv) was
added dropwise, at room temperature, to a solution of compound 37
(1 g, 2.4 mmol, 1.0 equiv), titanium isopropoxide (1 mL, 3.4 mmol,
1.4 equiv) and tetrahydrofuran (10 mL). The reaction was stirred
overnight, when LC/MS analysis indicated the presence of starting
material. Additional titanium isopropoxide (1 mL, 3.4 mmol, 1.4
equiv) and 2.7M ethylmagnesium chloride in tetrahydrofuran (2.5 mL,
6.8 mmol, 2.8 equiv) were added. The reaction was quenched with
water (10 mL) and extracted with ethyl acetate (3.times.10 mL). The
combined organic layers were dried over sodium sulfate and
concentrated under reduced pressure. The residue was purified on an
AnaLogix (SF 15-24 g) column, eluting with a gradient of 0 to 40%
ethyl acetate in heptanes. The product was subjected to further
purification by preparative HPLC, using a gradient of 0% to 95%
acetonitrile (0.1% formic acid) in water (0.1% formic acid), to
give compound 48 as a light yellow solid (50 mg, 5% yield).
Example 27
Synthesis of
4-[(Z)-2-[1-(4-isopropoxyphenyl)benzimidazol-5-yl]vinyl]benzonitrile
(compound 49) and
1-[4-[(Z)-2-[1-(4-isopropoxyphenyl)benzimidazol-5-yl]vinyl]phenyl]cyclopr-
opanamine (compound 54)
4-[(Z)-2-[1-(4-isopropoxyphenyl)benzimidazol-5-yl]vinyl]benzonitrile
(compound 49) and
1-[4-[(Z)-2-[1-(4-isopropoxyphenyl)benzimidazol-5-yl]vinyl]phenyl]cyclopr-
opanamine (compound 54) were synthesized according to the following
scheme:
##STR00092##
Synthesis of
4-[(Z)-2-[1-(4-isopropoxyphenyl)benzimidazol-5-yl]vinyl]benzonitrile
(compound 49)
To a suspension of (4-cyanobenzyl)triphenylphosphonium chloride
(9.50 g, 22.95 mmol, 1.2 equiv) in anhydrous tetrahydrofuran (380
mL) at 0.degree. C. was added a 60% dispersion of sodium hydride in
mineral oil (1.53 g, 38.24 mmol, 2 equiv). The reaction was stirred
at 0.degree. C. for 1 hour, then cooled to -78.degree. C. Compound
39-2 (5.35 g, 19.12 mmol, 1 equiv) was added and the reaction was
slowly warmed to room temperature and stirred for 16 hours. The
reaction was filtered, concentrated under reduced pressure and the
residue was purified on an AnaLogix automated chromatography system
(dry-loaded), eluting with a gradient of 5 to 40% ethyl acetate in
heptanes, to give compound 49 as a white solid (1.57 g, 22%
yield).
Synthesis of
1-[4-[(Z)-2-[1-(4-isopropoxyphenyl)benzimidazol-5-yl]vinyl]phenyl]cyclopr-
opanamine (compound 54)
To a solution of compound 49 (1 g, 2.6 mmol, 1.0 equiv) and
titanium tetra-isopropoxide (18 mL, 6.3 mmol, 2.4 equiv) in
tetrahydrofuran (50 mL) was added dropwise 2.7M ethylmagnesium
chloride (4.3 mL, 11.6 mmol, 4.4 equiv) at -78.degree. C. The
reaction was allowed to slowly warm to room temperature for 1 hour.
Boron trifluoride etherate (0.65 mL, 5.3 mmol, 2 equiv) was added,
stirred for 16 hours and then quenched with the sequential addition
of 1N HCl (aq.) (20 mL) and 10% sodium hydroxide (100 mL). The
mixture was extracted with ethyl acetate (3.times.20 mL) and the
combined organic layers were dried over sodium sulfate and
concentrated under reduced pressure. The residue was purified on an
AnaLogix automated chromatography system, eluting with a gradient
of 0 to 4% methanol in dichloromethane. The product was subject to
a second purification by preparative HPLC using a gradient of 0% to
95% acetonitrile (0.1% formic acid) in water (0.1% formic acid).
The resulting salt was adjusted to pH 8 with 10% sodium hydroxide.
The aqueous layer was extracted with MTBE (3.times.20 mL), dried
over sodium sulfate and concentrated under reduced pressure. The
residue was again purified on an AnaLogix automated chromatography
system, eluting with a gradient of 0 to 4% methanol in
dichloromethane, to give compound 54 as an off-white wax (63 mg, 6%
yield).
Example 28
Synthesis of
2-[4-[(Z)-2-[1-(4-isopropoxyphenyl)benzimidazol-5-yl]vinyl]phenyl]propan--
2-amine (compound 60)
2-[4-[(Z)-2-[1-(4-isopropoxyphenyl)benzimidazol-5-yl]vinyl]phenyl]propan--
2-amine (compound 60) was synthesized according to the following
scheme:
##STR00093##
Synthesis of
(Z)-5-(4-(2-azidopropan-2-yl)styryl)-1-(4-isopropoxyphenyl)-1H-benzo[d]im-
idazole (compound 60-1)
Trifluoroacetic acid (0.5 mL) was added dropwise at room
temperature to a suspension of compound 38 (0.39 g, 0.95 mmol, 1
equiv) and sodium azide (0.14 g, 2.08 mmol, 2.2 equiv) in
chloroform (1 mL). The reaction was stirred at room temperature for
16 hours and then quenched with saturated ammonium hydroxide (5
mL). The mixture was extracted with dichloromethane (3.times.5 mL)
and the combined organic layers were dried over sodium sulfate,
filtered, and concentrated under reduced pressure to give compound
60-1 as an orange oil (0.42 g, >99% yield), which was used
directly in the next step.
Synthesis of
2-[4-[(Z)-2-[1-(4-isopropoxyphenyl)benzimidazol-5-yl]vinyl]phenyl]propan--
2-amine (compound 60)
Compound 60-1 (0.42 g, 0.95 mmol, 1 equiv) and triphenylphosphine
(0.27 g, 1.05 mmol, 1.1 equiv) were heated in a mixture of THF (2
mL) and water (0.2 mL) at 50.degree. C. for 16 hours. The reaction
was concentrated under reduced pressure and the residue was
purified on an AnaLogix automated chromatography system, eluting
with a gradient of 0 to 10% methanol in dichloromethane, to give
compound 60 as a clear wax (59 mg, 15% yield).
Example 29
Synthesis of
3-(4-Ethoxybenzyl)-N-(4-ethylbenzyl)-3H-imidazo[4,5-b]pyridin-6-amine
(compound 62)
3-(4-Ethoxybenzyl)-N-(4-ethylbenzyl)-3H-imidazo[4,5-b]pyridin-6-amine
(compound 62) was synthesized according to the following
scheme:
##STR00094##
Synthesis of 5-Bromo-N-(4-ethoxybenzyl)-3-nitropyridin-2-amine
(compound 62-2)
To a stirred solution of 2,5-dibromo-3-nitropyridine (1 g, 3.5
mmol, 1 equiv) in ethanol (10 mL) was added a
(4-ethoxyphenyl)methanamine (580 .mu.L, 3.9 mmol, 1.1 equiv) and
triethylamine (1 mL, 7.1 mmol, 2 equiv). The reaction mixture was
allowed to stir at room temperature for 18 hours, at which time
LC-MS indicated the reaction was complete. The suspension was
filtered and the solid washed with ethanol (2.times.5 mL) to
produce compound 62-2 as a yellow solid (1.1 g, 92% yield).
Synthesis of 5-Bromo-N2-(4-ethoxybenzyl)pyridine-2,3-diamine
(compound 62-3)
A solution of compound 62-2 (1.1 g, 3.1 mmol, 1 equiv) in a 1:1
mixture of ethyl acetate/tetrahydrofuran (20 mL) was heated to
60.degree. C. Tin(II) chloride dihydrate (2.5 g, 11 mmol, 3.5
equiv) was added portion wise and the reaction was stirred at
60.degree. C. overnight. The reaction mixture was cooled to room
temperature and diluted with saturated aqueous sodium bicarbonate
(50 mL). The mixture was filtered through Celite and the pad was
washed with ethyl acetate (2.times.50 mL). The layers were
separated and the aqueous phase was washed with ethyl acetate
(2.times.50 mL). The combined organic phases were dried over sodium
sulfate and evaporated to dryness under reduce pressure to produce
compound 62-3 as a brown oil (1 g, quantitative yield).
Synthesis of 6-Bromo-3-(4-ethoxybenzyl)-3H-imidazo[4,5-b]pyridine
(compound 62-4)
Compound 62-3 (1 g, 3.1 mmol, 1 equiv) was dissolved in
2-methoxyethanol (80 mL) and formamidine acetate (1.0 g, 9.3 mmol,
3 equiv) was added. The reaction was heated at reflux overnight, at
which time LC-MS indicated the reaction was complete. The reaction
was cooled to room temperature and concentrated to dryness. The
residue was suspended in water (30 ml) and stirred for 1 h. The
suspension was filtered and the solid was washed with water
(2.times.5 mL). The material was dried in a vacuum oven at
45.degree. C. overnight to give compound 62-4 as a tan solid (0.8
g, 81% yield).
Synthesis of
3-(4-Ethoxybenzyl)-N-(4-ethylbenzyl)-3H-imidazo[4,5-b]pyridin-6-amine
(compound 62)
A solution of compound 62-4 (0.5 g, 1.5 mmol, 1 equiv),
tris(dibenzylideneacetone) palladium(0) chloroform adduct (0.08 g,
0.08 mmol, 0.05 equiv), racemic BINAP (0.09 g, 0.15 mmol, 0.1
equiv), (4-ethylphenyl)methanamine (325 .mu.L, 2.3 mmol, 1.5
equiv), and sodium tert-butoxide (0.22 g, 2.3 mmol, 1.5 equiv) in
toluene (30 mL) was degassed with a stream of nitrogen for 10
minutes. The reaction was heated at reflux overnight, at which time
LC-MS indicated the reaction was complete. The reaction was diluted
with ethyl acetate (50 mL), filtered through Celite and the pad was
washed with ethyl acetate (50 mL). The filtrate was concentrated
under reduced pressure, diluted with water (50 mL) and extracted
with ethyl acetate (3.times.50 mL). The organic layers were
combined, dried over sodium sulfate, and evaporated under reduce
pressure. The compound was purified on an AnaLogix (SF 15-24 g)
column. The gradient utilized for the purification was 2 minutes
isocratic at 30% ethyl acetate in heptanes followed by a ramp to
80% ethyl acetate in heptanes over 40 minutes to give compound 62
as a tan solid (100 mg, 17% yield).
Example 30
Synthesis of 1-(4-Ethoxyphenyl)-N-(4-ethylbenzyl)-1H-indol-5-amine
(compound 63)
1-(4-Ethoxyphenyl)-N-(4-ethylbenzyl)-1H-indol-5-amine (compound 63)
was synthesized according to the following scheme:
##STR00095##
Synthesis of N-(4-Ethylbenzyl)-1H-indol-5-amine (compound 63-2)
To a stirred solution of 5-aminoindole (0.73 g, 5.5 mmol, 1 equiv)
in methanol (10 mL) was added 4-ethylbenzaldehyde (0.74 g, 5.5
mmol, 1.1 equiv). The reaction mixture was allowed to stir at room
temperature for 30 minutes at which time sodium borohydride (0.21
g, 5.5 mmol, 1 equiv) was added and stirring continued for 30
minutes. Upon completion of the reaction, saturated aqueous sodium
bicarbonate (4 mL) was added and the solution was stirred for 30
minutes. This reaction mixture was poured into dichloromethane (10
mL) and extracted. The dichloromethane was separated, dried over
sodium sulfate and removed under reduced pressure. This material
(compound 63-2) was used in the next step without further
purification.
Synthesis of 1-(4-Ethoxyphenyl)-N-(4-ethylbenzyl)-1H-indol-5-amine
(compound 63)
Crude compound 63-2 was dissolved in N,N'-dimethylformamide (10 mL)
along with 4-iodophenetole (1.37 g, 5.5 mmol, 1 equiv), copper
iodide (0.105 g, 0.55 mmol, 0.1 equiv),
N,N,N',N'-tetramethylenediamine (0.126 g, 1.10 mmol, 0.2 equiv),
and potassium carbonate (1.14 g, 8.25 mmol, 1.5 equiv). The mixture
was heated at 100.degree. C. for 48 hours. Upon completion, the
mixture was concentrated under reduced pressure and the residue was
purified by silica gel chromatography using a gradient of 0-50%
ethyl acetate in heptanes to give compound 63 as a white solid (117
mg, 6% yield).
Example 31
Synthesis of 3-(4-Ethoxyphenyl)-N-(4-ethylbenzyl)-1H-indol-6-amine
(compound 64)
3-(4-Ethoxyphenyl)-N-(4-ethylbenzyl)-1H-indol-6-amine (compound 64)
was synthesized according to the following scheme:
##STR00096##
Synthesis of tert-Butyl 1H-indol-6-ylcarbamate (compound 64-2)
To a stirred solution of 1H-indol-6-amine (1.12 g, 8.5 mmol, 1
equiv) was added di-tert-butyl dicarbonate (1.95 g, 8.9 mmol, 1.05
equiv) in tetrahydrofuran (6 mL). Saturated aqueous sodium
bicarbonate (6 mL) was added and the reaction was stirred at room
temperature for 18 hours. The layers were separated and the aqueous
layer was extracted with ethyl acetate (3.times.5 mL). The organic
layers were combined, dried over sodium sulfate and concentrated
under reduced pressure to give compound 64-2 as a white solid (2.2
g, 97% yield).
Synthesis of tert-Butyl 3-iodo-1H-indol-6-ylcarbamate (compound
64-3)
To a solution of compound 64-2 (2.3 g, 10 mmol, 1 equiv) in
dimethyl formamide (10 mL) was added potassium carbonate powder
(3.5 g, 25 mmol, 2.5 equiv) followed by a solution of iodine (2.7
g, 10.5 mmol, 1.05 equiv) in dimethyl formamide (10 mL). The
reaction was stirred at room temperature for 3 h and then poured
into saturated brine (200 mL) and methyl tert-butyl ether (100 mL).
The layers were separated and the aqueous phase was extracted with
methyl tert-butyl ether (3.times.50 mL). The organic layers were
combined, back extracted with brine (3.times.100 mL), and dried
over sodium sulfate. The extracts were filtered and concentrated
under reduced pressure to give compound 64-3 as a yellow solid (3.5
g, 99% yield).
Synthesis of tert-Butyl
6-(bis(tert-butoxycarbonyl)amino)-3-iodo-1H-indole-1-carboxylate
(compound 64-4)
To a solution of compound 64-3 (3.5 g, 10 mmol, 1 equiv) in
dichloromethane (50 mL) was added di-tert-butyl dicarbonate (4.5 g,
21 mmol, 2.5 equiv) followed by triethylamine (3.5 mL, 25 mmol, 2.5
equiv) and N,N-4-dimethyl aminopyridine (120 mg, 1 mmol, 0.1
equiv). The solution began to reflux on its own upon addition of
the dimethylaminopyridine. The reaction was stirred at room
temperature for 18 hours. At that time, the reaction was
concentrated under reduced pressure to a thick white residue. The
residue was purified by column chromatography utilizing a gradient
of 0-50% ethyl acetate in heptanes to produce compound 64-4 as a
white solid (3.5 g, 63% yield).
Synthesis of 3-(4-Ethoxyphenyl)-1H-indol-6-amine (compound
64-5)
A suspension of compound 64-4 (1.12 g, 2 mmol, 1 equiv),
Pd(PPh.sub.3).sub.4 (116 mg, 0.1 mmol, 0.05 equiv),
4-ethoxyphenylboronic acid (350 mg, 2.1 mmol, 1.05 equiv), and
sodium carbonate (424 mg, 4 mmol, 2 equiv) in a 3:1 mixture of
dioxane and water (20 mL) was degassed with a stream of nitrogen
for 10 minutes. The reaction was heated at reflux for 3 h, at which
time LC-MS indicated the reaction was complete. Ethyl acetate (20
mL) was added and the layers were separated. The organic layer was
dried over sodium sulfate, filtered through silica gel (2 g) and
the silica gel was washed with ethyl acetate (15 mL). The filtrates
were evaporated under reduce pressure and the residue was purified
by column chromatography eluting with a gradient of 0-25% ethyl
acetate in heptanes. This purified material was dissolved in
dioxane (10 mL) and a 4.0M hydrogen chloride solution in dioxane
(3.5 mL) was added. The reaction was stirred at room temperature
over the weekend. The solvent was removed under reduced pressure
and water (50 mL) was added. The pH was adjusted to 8 with 1N
sodium hydroxide and the aqueous phase was extracted with a 3:1
mixture of ethyl acetate:tetrahydrofuran (3.times.20 mL). The
organic layers were combined, dried over sodium sulfate, and
concentrated under reduced pressure to give compound 64-5 as an off
white solid (270 mg, 54% yield).
Synthesis of 3-(4-Ethoxyphenyl)-N-(4-ethylbenzyl)-1H-indol-6-amine
(compound 64)
To a solution of compound 64-5 (270 mg, 1.07 mmol, 1 equiv) in
methanol was added 4-ethyl benzaldehyde (250 .mu.L, 1.7 mmol, 1.7
equiv). Then, acetic acid (5 drops) was added and the reaction was
stirred at room temperature for 2 hours. Sodium borohydride (250
mg) was added until LC analysis showed complete conversion of the
peak assumed to be the imine. The product from 4 runs was
chromatographed on an AnaLogix 12 g column using a gradient of
15-30% ethyl acetate in heptanes as the eluent. The product
containing fractions were combined and concentrated under reduced
pressure. This residue was triturated with 10% ethyl acetate in
heptanes (5 mL) and the solid dried to give compound 64 as a yellow
solid (58 mg, 14% yield).
Example 32
Synthesis of
3-(4-Ethoxyphenyl)-N-(4-ethylbenzyl)imidazo[1,2-a]pyridin-7-amine
(compound 65)
3-(4-Ethoxyphenyl)-N-(4-ethylbenzyl)imidazo[1,2-a]pyridin-7-amine
(compound 65) was synthesized according to the following
scheme:
##STR00097##
Synthesis of 4-Chloropyridin-2-amine (compound 65-2)
To a stirred solution of tert-butyl 4-chloropyridin-2-ylcarbamate
(2 g, 8.7 mmol, 1 equiv) was added a 4N solution of hydrogen
chloride in dioxane (10 mL, 40 mmol, 4.6 equiv). The solution was
allowed to stir for 18 hours at room temperature. The reaction was
concentrated under reduced pressure to give compound 65-2 (HCl) as
a reddish yellow solid (1.5 g, 100% yield).
Synthesis of 7-Chloroimidazo[1,2-a]pyridine (compound 65-3)
To a suspension of compound 65-2 (HCl) in ethanol (15 mL) was added
sodium bicarbonate powder (3.3 g, 38.4 mmol, 4 equiv) and a 50%
solution of chloroacetaldehyde in water (2.26 g, 14.4 mmol, 1.5
equiv). The reaction was heated at reflux for 4 hours and stirred
at room temperature for 16 hours. The reaction was concentrated
under reduced pressure and the residue was dissolved in water (10
mL) and ethyl acetate (10 mL). The layers were separated and the
aqueous phase was extracted with ethyl acetate (2.times.5 mL). The
organic layers were combined, dried over sodium sulfate, filtered
and concentrated to give compound 65-3 as a dark yellow oil (980
mg, 89% yield).
Synthesis of 7-Chloro-3-iodoimidazo[1,2-a]pyridine (compound
65-4)
To a solution of compound 65-3 (450 mg, 2.9 mmol, 1 equiv) in
dimethyl formamide (4.5 mL) was added N-iodosuccinimide (700 mg,
3.1 mmol, 1.05 equiv). The reaction was stirred at room temperature
for 6 hours followed by the addition of water (20 ml) and ethyl
acetate (20 ml). The layers were separated and the aqueous phase
was extracted with ethyl acetate (3.times.5 ml). The organic layers
were combined, dried over sodium sulfate, filtered and concentrated
under reduced pressure to a black residue. The residue from 2 runs
was chromatographed on an AnaLogix 8 g column using a gradient of
0-70% ethyl acetate in heptanes. The product containing fractions
were combined and washed with saturated sodium thiosulfate solution
(2.times.20 ml) to remove the remaining iodine color. The fractions
were concentrated to give compound 65-4 as a white solid (829 mg,
50% yield).
Synthesis of 7-Chloro-3-(4-ethoxyphenyl)imidazo[1,2-a]pyridine
(compound 65-5)
A suspension of compound 65-4 (200 mg, 0.72 mmol, 1 equiv),
Pd(PPh.sub.3).sub.4 (41 mg, 0.036 mmol, 0.05 equiv),
4-ethoxyphenylboronic acid (121.5 mg, 0.73 mmol, 1.02 equiv), and
sodium carbonate (152 mg, 1.4 mmol, 2 equiv) in 3:1 mixture of
dioxane and water (20 mL) was degassed with a stream of nitrogen
for 10 minutes. The reaction was heated at 90.degree. C. for 3 h,
at which time LC-MS indicated the reaction was complete. Ethyl
acetate (10 mL) was added and the layers were separated. The
organic layer was dried over sodium sulfate, filtered through
silica gel (2 g) and the silica gel was washed with ethyl acetate
(15 mL). The filtrates were evaporated under reduce pressure and
the product was triturated with methyl tert-butyl ether (3 mL) to
give compound 65-5 as an off white solid. (130 mg, 70% yield)
Synthesis of
3-(4-Ethoxyphenyl)-N-(4-ethylbenzyl)imidazo[1,2-a]pyridin-7-amine
(compound 65)
A suspension of compound 65-5 (162 mg, 0.59 mmol, 1 equiv),
tris(dibenzylideneacetone) palladium(0) chloroform adduct (31 mg,
0.03 mmol, 0.05 equiv), racemic BINAP (37 mg, 0.059 mmol, 0.1
equiv), 4-ethyl benzylamine (130 .mu.L, 0.89 mmol, 1.5 equiv), and
sodium tert-butoxide (86 mg, 0.89 mmol, 1.5 equiv) in toluene (15
mL) was degassed with a stream of nitrogen for 5 minutes. The
reaction was heated at reflux for 18 h, at which time LC-MS
indicated the reaction was complete. The mixture was concentrated
under reduced pressure, diluted with water (20 mL) and extracted
with ethyl acetate (3.times.10 mL). The organic layers were
combined, dried over sodium sulfate, and evaporated under reduced
pressure. The product was chromatographed on an AnaLogix 8 g column
using a gradient of 20-100% ethyl acetate in heptanes as the eluent
to give compound 65 as a brown sticky solid (48 mg, 27% yield).
Example 33
Synthesis of
1-(4-ethoxyphenyl)-N-(4-ethylbenzyl)-1H-pyrrolo[2,3-b]pyridin-5-amine
(compound 66)
1-(4-ethoxyphenyl)-N-(4-ethylbenzyl)-1H-pyrrolo[2,3-b]pyridin-5-amine
(compound 66) was synthesized according to the following
scheme:
##STR00098##
Synthesis of N-(4-ethylbenzyl)-1H-pyrrolo[2,3-b]pyridin-5-amine
(compound 66-2)
To a stirred solution of 1H-pyrrolo[2,3-b]pyridin-5-amine (0.5 g,
3.8 mmol, 1 equiv) in methanol (20 ml) was added 4-ethyl
benzaldehyde (566 .mu.L, 4.1 mmol, 1.1 equiv). Acetic acid (5
drops) was added and the reaction was stirred for 2 hours during
which time a white solid formed. Dichloromethane (30 mL) was added
to dissolve the entire solid. Sodium borohydride (700 mg) was added
portionwise until all intermediate imine was consumed by LC-MS
analysis. The reaction was poured into water (50 mL) and the layers
were separated. The aqueous phase was extracted with
dichloromethane (3.times.10 mL). The organic layers were combined,
dried over sodium sulfate, and concentrated under reduced pressure.
This residue was triturated with methyl tert-butyl ether (2.times.8
mL) to give compound 66-2 as an off-white solid (640 mg, 68%
yield).
Synthesis of
1-(4-ethoxyphenyl)-N-(4-ethylbenzyl)-1H-pyrrolo[2,3-b]pyridin-5-amine
(compound 66)
Compound 66-2 (300 mg, 1.2 mmol, 1 equiv), 4-iodophenatol (310 mg,
1.26 mmol, 1.05 equiv) and potassium carbonate powder (124 mg, 1.80
mmol, 1.5 equiv) were suspended in a 5:1 mixture of dimethyl
formamide:water (6 mL). Copper(I) iodide (12 mg, 0.12 mmol, 0.1
equiv) and tetramethylethylene diamine (40 .mu.L, 0.24 mmol, 0.2
equiv) were added and the reaction was stirred at reflux for 48
hours. The reaction was poured into water (50 mL) and extracted
with ethyl acetate (3.times.25 ml). The organic layers were
combined, dried over sodium sulfate, and concentrated under reduced
pressure. The residue was chromatographed on an AnaLogix 24 g
column using 20-100% ethyl acetate in heptanes as the eluent. The
product containing fractions were combined. The starting material
fractions were combined and resubjected to the reaction to get more
material. The product from 4 runs was combined to give compound 66
as an off-white solid (50 mg, 7.3% yield).
Example 34
Synthesis of
1-(4-Ethoxyphenyl)-5-(4-ethylbenzylamino)-1H-benzo[d]imidazole
3-oxide (compound 67)
1-(4-Ethoxyphenyl)-5-(4-ethylbenzylamino)-1H-benzo[d]imidazole
3-oxide (compound 67) was synthesized according to the following
scheme:
##STR00099##
Synthesis of N-(4-Ethoxyphenyl)formamide (compound 67-2)
p-Phenetidine (1 g, 7.29 mmol, 1.0 equiv) and formic acid (0.55 mL,
14.58 mmol, 2.0 equiv) were heated to 50.degree. C. for 6 hours and
then stirred at room temperature overnight. The reaction mixture
was poured into water (100 mL), the mixture stirred vigorously for
15 min and the resulting oily suspension extracted with tert-butyl
methyl ether (100 mL). The organic phase was washed with saturated
aqueous sodium bicarbonate solution (100 mL), water (100 mL) and
brine (100 mL), dried over sodium sulfate and concentrated under
reduced pressure to give a light brown syrup (1.16 g). The crude
product was purified on an AnaLogix (SF 25-80 g) column using a
gradient of 0-100% ethyl acetate in heptanes to give compound 67-2
as an off-white solid (0.98 g, 81% yield).
Synthesis of N-(2,4-Dinitrophenyl)-N-(4-ethoxyphenyl)-formamide
(compound 67-3)
To a solution of 2,4-dinitrofluorobenzene (0.37 g, 2.0 mmol, 1.0
equiv) and compound 67-2 (0.33 g, 2.0 mmol, 1.0 equiv) in anhydrous
dimethyl sulfoxide (12 mL) was added cesium carbonate (0.65 g, 2.0
mmol, 1.0 equiv). The reaction mixture was stirred at room
temperature under nitrogen for 19 hours. The reaction mixture was
poured into 1.0 M aqueous hydrochloric acid solution (100 mL) and
the resulting suspension extracted with ethyl acetate (100 mL). The
organic phase was washed with 1.0 M aqueous sodium hydroxide
solution (2.times.100 mL), water (100 mL) and brine (100 mL), dried
over sodium sulfate and concentrated under reduced pressure to give
an orange syrup (0.33 g). The crude product was purified on an
AnaLogix (SF 25-40 g) column using a gradient of 0-100% ethyl
acetate in heptanes to give compound 67-3 as a yellow syrup (135
mg, 21% yield).
Synthesis of 5-Amino-1-(4-ethoxyphenyl)-1H-benzo[d]imidazole
3-oxide (compound 67-4)
To platinum dioxide (30 mg) was added a solution of compound 67-3
(135 mg, 0.408 mmol, 1.0 equiv) in absolute ethanol (20 mL)
followed by 4.0 M hydrogen chloride in dioxane (0.26 mL, 1.02 mmol,
2.5 equiv) and the mixture was hydrogenated at 15 psi for 2.5
hours. The mixture was filtered through Celite, washing through
with ethyl acetate, and the filtrate concentrated under reduced
pressure to give a pink solid. The crude product was dissolved in
dichloromethane (30 mL), 1.0 M aqueous sodium carbonate solution (5
mL) was added and the biphasic mixture stirred vigorously for 2
hours. Following the addition of a saturated brine solution (20
mL), the organic phase was separated, washed with saturated brine
(20 mL), dried over sodium sulfate and concentrated under reduced
pressure to give a brown solid (100 mg). The crude product was
purified on an AnaLogix (SF 15-24 g) column using a gradient of
0-10% methanol in dichloromethane followed by a gradient of 0-100%
ethanol in dichloromethane to give compound 67-4 as a brown solid
(28.2 mg, 26% yield).
Synthesis of
1-(4-Ethoxyphenyl)-5-(4-ethylbenzylamino)-1H-benzo[d]imidazole
3-oxide (compound 67)
To a solution compound 67-4 (24.1 mg, 0.089 mmol, 1.0 equiv) in
anhydrous methanol (1 mL) at room temperature under nitrogen was
added 4-ethylbenzaldehyde (0.014 mL, 0.098 mmol, 1.1 equiv) and the
reaction mixture stirred at room temperature for 6 hours. Sodium
borohydride (3.4 mg, 0.089 mmol, 1.0 equiv) was added and the
reaction mixture stirred at room temperature for an additional 15
minutes. The reaction was quenched by the addition of a saturated
aqueous ammonium chloride solution (4 mL), the mixture stirred
vigorously for 5 minutes and extracted with ethyl acetate (30 mL).
The organic phase was separated, washed with brine (2.times.20 mL),
dried over sodium sulfate and concentrated under reduced pressure
to give a yellow solid. The crude product was purified on an
AnaLogix (SF 15-24 g) column using a gradient of 0-10% methanol in
dichloromethane to give compound 67 as a tan solid (26.2 mg, 76%
yield).
Example 35
Determining Antiviral Activity of Compounds of the Invention
Work with Lassa fever virus presents significant logistical and
safety issues due to the requirement for maximum laboratory
containment (BSL-4). Therefore, surrogate assays for anti-Lassa
fever virus activity were developed that would be suitable for
evaluating large numbers of compounds under less-restrictive BSL-2
laboratory conditions. One such assay was developed to identify
compounds that can block Lassa virus entry into the host cell. This
assay uses only the envelope glycoprotein from Lassa fever virus,
not the virus itself, and thus can safely be performed under normal
BSL-2 conditions. The viral entry step is an attractive target for
the development of antiviral pharmaceuticals, because it is an
essential component of every viral life cycle. In addition, the
antiviral targets, the interaction between the viral envelope and
the host cell and subsequent structural rearrangement of the
envelope, are specific to the virus. Thus, effective inhibitors are
less likely to interfere with host processes.
Viral pseudotypes, which are generated by cotransfection of the
Lassa envelope and a replication-defective HIV provirus with a
luciferase reporter, are used to assess Lassa envelope function.
The provirus is engineered so that the HIV envelope is not
expressed, and thus heterologous viral envelope proteins are
acquired as budding viral particles nonspecifically capture cell
surface proteins. Pseudotypes prepared in this manner will infect
cells via the heterologous envelope and are commonly used to assay
functions of the heterologous envelope (2,9,26,31,33). Infection is
measured by the luciferase signal produced from the integrated HIV
reporter construct. The amount of infectious virus used to infect a
cell culture line is directly proportional, over several orders of
magnitude, to the luciferase-mediated luminescence produced in the
infected cells.
Benzimidazole compounds were screened for antiviral activity and
served as the basis for subsequent examination of the
structure-activity relationship. A number of very potent antiviral
compounds were identified as shown in Tables 3 and 4. For the
alkene linked analogs for which both cis and trans versions were
synthesized (compounds 1-25), compounds with the cis configuration
had submicromolar EC.sub.50 values, whereas only about half of the
analogs with the trans configuration displayed potency in the same
range. For compounds 27-33, it was apparent that the presence of a
carbon, oxygen, or sulfur linker did not have a large effect on
antiviral potency. The majority of the compounds included in Table
2 involved exploration of nitrogen atom positioning about the
bicyclic core. We were able to mostly retain submicromolar
antiviral potency throughout the study involving addition,
subtraction, and repositioning of nitrogen atoms.
The compounds disclosed herein were synthesized to improve
potencies, solubility and other properties. As indicated above,
Compound 2 is shown to be very potent with a submicromolar
EC.sub.50 value in the assay against Lassa GP-pseudotyped-virus in
293T cells (Table 3).
TABLE-US-00015 TABLE 3 Anti-Viral for compounds of Formula I of the
present invention. Activity (EC.sub.50 in .mu.M vs. pseudotyped
virus) A: EC.sub.50 < 1 .mu.M; B: 1 .ltoreq. EC.sub.50 < 10
.mu.M; C: 10 .ltoreq. EC.sub.50 < 50 .mu.M; D: EC.sub.50
.gtoreq. 50 .mu.M; n.d.: not determined Compound Lassa Machupo
Guanarito Junin Sabia VSVg 1 A A n.d. n.d. n.d. C 2 A A A A A C 3 B
n.d. n.d. n.d. n.d. C 4 A n.d. n.d. n.d. n.d. C 5 A A n.d. A A C 6
A n.d. n.d. n.d. n.d. C 7 A A n.d. A A C 8 A A n.d. A n.d. C 9 A A
n.d. A A C 10 A B n.d. A n.d. D 11 A A n.d. A n.d. C 12 C *Note 1
n.d. C n.d. **Note 2 13 A A n.d. A n.d. C 14 B n.d. n.d. n.d. n.d.
C 15 A n.d. n.d. n.d. A C 16 B n.d. n.d. n.d. n.d. C 17 A n.d. n.d.
n.d. A C 18 A n.d. n.d. B n.d. C 19 A A n.d. A A C 20 A n.d. n.d.
n.d. n.d. B 21 A A n.d. A A C 22 A A n.d. A n.d. C 23 B n.d. n.d.
n.d. n.d. D 24 A A n.d. A A C 25 B n.d. n.d. n.d. n.d. D 26 B C
n.d. B n.d. C 27 A A A A A D 28 A A n.d. A n.d. D 29 A A n.d. A
n.d. C 30 A A n.d. A n.d. C 31 A A A A A C 32 A A n.d. A A C 33 A A
A A A C 34 A A n.d. A n.d. C 35 A A n.d. n.d. n.d. C 36 A A n.d. A
n.d. C 37 A A n.d. A n.d. C 38 A A n.d. A n.d. B 39 A A n.d. A n.d.
B 40 A A n.d. A n.d. C 41 A A n.d. n.d. n.d. C 42 A A n.d. n.d.
n.d. B 43 A A n.d. n.d. n.d. B 44 A n.d. n.d. n.d. n.d. C 45 C A
n.d. A B D 46 A A n.d. n.d. n.d. B 47 A A n.d. n.d. n.d. B 48 A A
n.d. A n.d. C 49 A n.d. n.d. n.d. n.d. C 50 A A n.d. A n.d. B 51 A
A n.d. A n.d. B 52 A A n.d. A n.d. B 53 A A n.d. A n.d. B 54 A A
n.d. A n.d. C 55 A n.d. n.d. n.d. n.d. D 56 A A n.d. n.d. n.d. B 57
A A n.d. n.d. n.d. B 58 B A n.d. A n.d. C 59 A A n.d. A n.d. B 60 A
A n.d. A n.d. D 61 A A n.d. A A C *Note 1: EC.sub.50 = 51 .mu.M
**Note 2: EC.sub.50 = 196 .mu.M
TABLE-US-00016 TABLE 4 Anti-Viral for compounds of Formula II of
the present invention. Activity (EC.sub.50 in .mu.M vs. pseudotyped
virus) A: EC.sub.50 < 1 .mu.M; B: 1 .ltoreq. EC.sub.50 < 10
.mu.M; C: 10 .ltoreq. EC.sub.50 < 50 .mu.M; D: EC.sub.50
.gtoreq. 50 .mu.M; n.d.: not determined Compound Lassa Machupo
Guanarito Junin Sabia VSVg 62 B B n.d. n.d. n.d. B 63 A A n.d. n.d.
n.d. C 64 A A n.d. A n.d. C 65 A A n.d. A n.d. B 66 A B n.d. n.d.
n.d. D 67 A A n.d. A n.d. C
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All references cited herein are herein incorporated by reference in
their entirety for all purposes.
The invention has been described in terms of preferred embodiments
thereof, but is more broadly applicable as will be understood by
those skilled in the art.
* * * * *